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Mol. Cells 2020; 43(2): 188-197

Published online February 3, 2020

https://doi.org/10.14348/molcells.2019.0310

© The Korean Society for Molecular and Cellular Biology

Complex Interplay between the RUNX Transcription Factors and Wnt/β-Catenin Pathway in Cancer: A Tango in the Night

Kerri Sweeney1 , Ewan R. Cameron2,* , and Karen Blyth1,3,*

Author Info. +

1CRUK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK, 2Glasgow Veterinary School, University of Glasgow, Glasgow G61 1QH, UK, 3Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK

Correspondence to : Ewan.Cameron@glasgow.ac.uk (ERC); Karen.Blyth@glasgow.ac.uk (KB)

Received: December 12, 2019; Accepted: December 19, 2019

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

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Cells are designed to be sensitive to a myriad of external cues so they can fulfil their individual destiny as part of the greater whole. A number of well-characterised signalling pathways dictate the cell’s response to the external environment and incoming messages. In healthy, well-ordered homeostatic systems these signals are tightly controlled and kept in balance. However, given their powerful control over cell fate, these pathways, and the transcriptional machinery they orchestrate, are frequently hijacked during the development of neoplastic disease. A prime example is the Wnt signalling pathway that can be modulated by a variety of ligands and inhibitors, ultimately exerting its effects through the β-catenin transcription factor and its downstream target genes. Here we focus on the interplay between the three-member family of RUNX transcription factors with the Wnt pathway and how together they can influence cell behaviour and contribute to cancer development. In a recurring theme with other signalling systems, the RUNX genes and the Wnt pathway appear to operate within a series of feedback loops. RUNX genes are capable of directly and indirectly regulating different elements of the Wnt pathway to either strengthen or inhibit the signal. Equally, β-catenin and its transcriptional co-factors can control RUNX gene expression and together they can collaborate to regulate a large number of third party co-target genes.

Keywords cancer, RUNX1, RUNX2, RUNX3, Wnt, β-catenin

INTRODUCTION

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Cells consult their extracellular environment, and the growth-regulating signals within it, during a discrete window of time in G1 phase of the cell cycle. Once cells have moved through this window, they proceed through S, G2, and M phases. However, if growth factors are removed before a specific time point, cells will fail to proceed toward S phase, and instead remain in G1 or revert to G0 phase (Pardee, 1974). This total dependence on extracellular signals, followed by entrance in late G1 into a state of relative independence, indicates that an important decision must be made before the end of G1. Precisely at this point, a cell must ‘make up its mind’ whether it will remain in G1, retreat from the active cycle into G0, or advance into late G1 and S phase. This critical decision is made at the restriction point or R-point (Malumbres and Barbacid, 2001; Pardee, 1974; Weinberg, 2014).

Time-lapse microscopy of asynchronously cycling Swiss 3T3 cells showed that cycling cells are sensitive to serum withdrawal for only the first 3 to 4 h after mitosis, implying that the R-point is within this interval (Zetterberg and Larsson, 1985). Subsequent studies revealed that the R-point occurs 3 to 4 h after mitogenic stimulation in most mammalian cells (Zetterberg et al., 1995). The concept of the R-point heralded the subsequent discovery of the cell-cycle engine (Nurse, 2000; Pardee, 1974; Sherr and Roberts, 1999). In addition, the R-point is deregulated in most cancer cells (Pardee, 1974; Weinberg, 2014). Therefore, understanding how cells make a fate decision at the R-point should provide insight into how the cell cycle is controlled and how tumors develop (Blagosklonny, 2006).

The DNA-binding transcription factor RUNX3, which plays pivotal roles in lineage determination, defends against oncogenic K-RAS–induced tumorigenesis (Ito et al., 2015). Deletion of Runx3 in mouse lung results in development of lung adenomas and accelerates oncogenic K-Ras–induced progression into adenocarcinomas (Lee et al., 2013). In mouse embryonic fibroblasts, Runx3 deletion perturbs the R-point, leading to transformation (Chi et al., 2017). Recent work showed that RUNX3 functions as a pioneer factor that plays key roles in R-point–associated induction of immediate early genes, including p21Waf/Cip (hereafter p21) and p19ARF (p14ARF in human, hereafter ARF). In this review, we summarize how RUNX3 contributes to the R-point decision in collaboration with histone modifiers, chromatin-remodeling complexes, the basal transcriptional machinery, and Polycomb group (PcG) proteins.

CHROMATIN DYNAMICS ASSOCIATED WITH R-POINT REGULATION

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When extracellular mitogenic signaling is maintained up to the R-point, transcription of R-point–associated target genes is activated (Chi et al., 2017). For a silent gene to be induced, the chromatin structure of its chromosomal locus must be opened. Chromatin structures and functions are modulated by covalent modification of specific residues within the amino-terminal tails of histones; the unique combination of modifications has been described as the histone code (Mills, 2010). Trithorax group (TrxG) proteins establish histone modifications that activate transcription, whereas PcG proteins establish histone modifications that repress transcription. TrxG proteins consist of two categories: histone modifiers (Strahl and Allis, 2000) and nucleosome remodelers (Vignali et al., 2000). TrxG histone modifiers include the mixed-lineage leukemia (MLL) protein, which methylates histone H3 at lysine 4 (H3K4-me), a histone mark that favors transcriptional activation. Nucleosome remodelers of TrxG complex contain SWI/SNF complex, which facilitate the binding of transcription factors and basal transcription machinery (Imbalzano et al., 1994). PcG complexes include two categories: Polycomb repressor complexes 1 and 2 (PRC1 and PRC2). The PRC2 complex contains Enhancer of Zeste Homolog 2 (EZH2), which trimethylates histone H3 at lysine 27 (H3K27-me), a characteristic of inactive chromatin (Cao et al., 2002).

Gain of PcG and loss of TrxG is a common theme in human cancer, indicating that PcG and TrxG are involved in regulation of tumor suppressors: PcG suppresses and TrxG activates tumor suppressors. ARF, which induces cell-cycle arrest and apoptosis by facilitating p53 activity in response to aberrant oncogene activation (Efeyan and Serrano, 2007; Kamijo et al., 1997; Palmero et al., 1998), is regulated by PcG and TrxG. During normal proliferation, PcG complexes (PRC1 and PRC2) and histone deacetylases (HDACs) bind the ARF locus, thereby inhibiting senescence. In response to oncogenic RAS, TrxG-mediated chromatin dynamics override PcG-mediated repression, thereby inducing ARF/p53-mediated senescence (Mills, 2010).

ENTERING INTO THE R-POINT AND ACTIVATION OF R-POINT–ASSOCIATED GENES

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Soon after mitogenic stimulation (within 1 h after stimulation), histone H4 and RUNX are acetylated by p300 acetyltransferase. BRD2 contains two bromodomains (BD1 and BD2), and each bromodomain interacts with a distinct protein: BD1 interacts with acetylated RUNX3, whereas BD2 interacts with acetylated histone H4. The p300–RUNX3–BRD2– histone complex is formed 1 to 2 h after serum stimulation, and binds to the promoters of the genes encoding p21 and ARF (Lee et al., 2019a). The complex dissociates 4 h later (Lee et al., 2019a). These observations suggest that a large complex containing RUNX3, BRD2, p300, and histone forms at the promoters of p21 and ARF at the R-point; within this complex, BRD2 grips both RUNX3 and histone through its two BDs. A schematic diagram of the complex formed at target loci soon after serum stimulation is shown in Figure 1.

BRD2 participates in multiprotein transcription complexes such as Mediator, recruits the SWI/SNF chromatin-remodeling complex (Denis et al., 2006), and allows RNA polymerase II to transcribe through the nucleosome (LeRoy et al., 2008). Interestingly, TAF1 and TBP form a complex with RUNX3 and BRD2 1 h after serum stimulation (Fig. 1). Similarly, MLL1/5 (activating histone modifiers) and the components of the SWI/SNF complex, Brg-1 and BAF-155, interact with RUNX3 and BRD2 simultaneously 1 to 2 h after serum stimulation, and subsequently dissociate (Fig. 1). These results demonstrate that the p300–RUNX3–BRD2–histone complex interacts with MLL1/5 as well as the SWI/SNF and TFIID complexes before the R-point.

ARF is a target of RUNX3 (Lee et al., 2013) that is critical for the life and death of cells; thus regulation of its expression could represent the R-point decision. Lee et al. (2019a) showed that MLL1/5, SWI/SNF, and TFIID are recruited to the ARF promoter locus, but not when the RUNX3 binding site is deleted. Consistent with this, MLL1/5, SWI/SNF, and TFIID are not recruited to the ARF promoter in H460 cells, which do not express RUNX3 but are recruited after ectopic expression of RUNX3. These results demonstrated that the MLL1/5, SWI/ SNF, and TFIID complexes are recruited to the ARF promoter, and that their recruitment is guided by RUNX3. The large RUNX3-containing complex formed before the R-point has been designated as the R-point–associated RUNX3-containing activator complex (Rpa-RX3-AC) (Fig. 1).

RUNX3 IS A PIONEER FACTOR OF THE R-POINT

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Interaction between Wnt and RUNX1 activity was reported over 20 years ago when it was shown that the β-catenin co-factor lymphoid enhancer factor 1 (LEF1) enhanced RUNX1 binding to chromatin and potentiated transcriptional activity of the T-cell receptor alpha (TCRα) enhancer (Mayall et al., 1997). Subsequently the mutual interdependence of these pathways has been described in systems as diverse as haematopoietic stem cells and ovaries, with RUNX1 capable of affecting the Wnt pathway at several discreet components of the pathway (Cheng et al., 2011; Friedman, 2009; Naillat et al., 2015; Wu et al., 2012).

The role of RUNX1 in leukaemia has been studied in the context of Wnt signalling whereby β-catenin is associated with the ability of leukaemia stem cells to self-renew. Treatment of haematopoietic progenitor cells with purified Wnt3a ligand increased the transcription of ETO and RUNX1 in addition to enhancing their spatial proximity. These events could precipitate translocation events between RUNX1 and ETO genes, resulting in the formation of the RUNX1-ETO fusion protein, which is a common mutation found in AML patients (Ugarte et al., 2015). Following from this work, it was found that, through Wnt3a treatment of leukaemia-derived cell lines and CD34+ progenitor cells, the distal P1 promoter of RUNX1 harboured a T-cell factor/lymphoid enhancer factor (TCF/LEF) binding site identifying this isoform as a bona fide target of β-catenin (Medina et al., 2016). It can be hypothesised that dysregulation of the Wnt pathway in haematopoietic progenitor cells leads to increased P1-Runx1 and ETO transcription and fusion, facilitating the development of leukaemia.

A number of studies have noted that RUNX1 mutation and putative loss of function is restricted to the ER+ subset of breast cancers (Banerji et al., 2012; Ellis et al., 2012). In an elegant study Chimge et al. (2016) provided one possible rationale for this observation when they showed that RUNX1 could act to block oestrogen-mediated inhibition of AXIN1 and that loss of RUNX1 could therefore release the oncogenic effects of oestrogen through stabilization of β-catenin. Conversely, in other cell lineages (for example, bone marrow), RUNX1 has been shown to potentiate β-catenin activity through other mechanisms, including the upregulation of activating Wnt ligands (Luo et al., 2019). However, studies in mouse skin demonstrated that the effects of RUNX1 on the Wnt signalling pathway are lineage dependent (Scheitz and Tumbar, 2013). As noted, reciprocal regulation between RUNX1 and β-catenin has been identified in a number of systems and may be expected given the complexity of gene regulation and cross talk between key regulators of survival, differentiation and proliferation. A more unique connection was reported by Jain et al. (2018) who suggested that RUNX1-induced changes in the structure of the cell membrane may render cells more sensitive to extracellular Wnt signals.

RUNX1 was found to be upregulated in colorectal cancer and this overexpression was linked to poorer survival in patients, as well as metastasis and induction of epithelial-to-mesenchymal transition (EMT) in colorectal cancer cells (Li et al., 2019). This aggressive phenotype was caused by RUNX1 activating the Wnt pathway via direct interaction with β-catenin, and interactions with the enhancer and promoter regions of KIT to promote its transcription and enhance Wnt/β-catenin signalling. Conversely, Runx1 deficiency in the mouse intestine was sufficient for tumour formation and significantly enhanced tumorigenesis in an ApcMin model of intestinal tumorigenesis (Fijneman et al., 2012). Gene expression analysis of colons from Runx1 KO mice revealed upregulations in genes previously described as transcriptional targets of β-catenin; Angiogenin4 (Ang4) and serine peptidase inhibitor, Kazal type 4 (Spink4); both of which were also previously found to be upregulated in Apc–/– colon cells (Andreu et al., 2008; Fijneman et al., 2012; Gregorieff et al., 2009). This potentially provides a mechanism by which Runx1 loss in the colon results in the expansion of stem cell populations and subsequent susceptibility to tumour initiation. The role of RUNX1/Wnt interactions in solid cancers may also extend to other major tumour types, for example high RUNX1 expression was predictive of a poor prognosis in clear cell renal cell carcinoma while Wnt signalling pathway was significantly enriched in tissues with high RUNX1 expression (Fu et al., 2019).

Interactions between RUNX2 and the Wnt pathway

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Bone is a highly dynamic tissue and both the Wnt signalling pathway and RUNX2 are integral to its formation and homeostatic control. As such, the bone field has been a rich source for studying the intricate relationship between these players. Runx2 is itself a downstream target of the canonical Wnt pathway (Fig. 2) and β-catenin/TCF activate Runx2 expression through a TCF binding site in the proximal promoter (Gaur et al., 2005), or through protein-protein interactions on Runx2 enhancer elements (Kawane et al., 2014). These studies reveal direct linkage between the osteogenic activity of the Wnt/β-catenin pathways and the key transcription factor mediating osteoblastic differentiation and bone development. Wnt induction of Runx2 is not restricted to osteoblasts and direct regulation by β-catenin/LEF1 has also been shown in chondrocytes (Dong et al., 2006). The importance of this applies to other systems, including pathophysiological processes inducing the calcification of vascular smooth muscle cells, where two other TCF binding sites were identified in the Runx2 proximal promoter (Cai et al., 2016).

Reciprocal regulation of major signalling pathways is a common theme with the Runx genes and in turn RUNX2 has been shown to regulate a variety of Wnt ligands (Qin et al., 2019), Wnt inhibitors (James et al., 2006; Mendoza-Villanueva et al., 2011; Perez-Campo et al., 2016) and TCF/LEF co-activators (Hoeppner et al., 2009; Mikasa et al., 2011), and in this way modulate the strength and specificity of the canonical Wnt pathway (Fig. 2). Although Wnt signalling and RUNX2 can clearly collaborate in bone development, it has been shown that enforced expression of RUNX2 in osteoblast cells can reduce levels of β-catenin and inhibit its transcriptional activity, perhaps to ensure fine tuning in the control of terminal differentiation (Haxaire et al., 2016). Intriguingly, GSK3β, the central player of the β-catenin destruction complex, also phosphorylates and negatively regulates RUNX2, suggesting a coordinated approach to the regulation of these transcription factors (Kugimiya et al., 2007).

In addition to their ability to regulate each other, β-catenin and RUNX2 also collaborate in the regulation of common target genes (Fig. 2). RUNX2 and canonical Wnt interact to regulate FGF18 (Reinhold and Naski, 2007) and Osteocalcin (Tang et al., 2009), whilst in other systems RUNX2 has been shown to be a fully paid-up member of the Wnt enhanceosome, the transcription complex that brings together TCFs and β β-catenin/LEF can block RUNX2 transcriptional activation by interacting directly with the DNA binding domain of RUNX2 (Kahler and Westendorf, 2003).

Wnt signalling has been implicated in different aspects of cancer development and progression. The role of this pathway in stem cell biology and tumour initiating cells is one area of intense interest. Our own work has shown that Runx2 expression is upregulated by Wnt3a; enriched in cells with the capacity to form mammospheres; and is required for mammary gland reconstitution in vivo (Ferrari et al., 2015). Importantly, RUNX2 was upregulated in Wnt-driven mammary tumours, suggesting that Runx2 was a Wnt target that could participate in both stem cell activity and tumour growth (Ferrari et al., 2015). The relationship between Wnt signalling and Runx genes in stem cells may extend to other lineages and may be ancestral as studies in C. elegans have revealed that the RUNX homologue RNT-1 acts on Wnt signalling through the suppression of POP-1 (TCF/LEF) to ensure stem cell renewal via symmetrical proliferation (van der Horst et al., 2019). At later stages of tumour development, RUNX2 has been associated with a more invasive phenotype of mammary cancer, an effect that may require co-activation of the Wnt pathway (Chimge et al., 2011). Conversely, RUNX2-induced inhibition of Wnt signalling in bone tissue may be involved in preparing the tumour site for colonisation (Mendoza-Villanueva et al., 2011).

Attenuation of Wnt signalling by RUNX3 in cancer

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A body of work has implicated RUNX3 as a tumour suppressor in the gastrointestinal tract as well as other cancer lineages, and a number of potential mechanisms have been proposed to explain this property. In this context RUNX3 was reported to form a complex with β-catenin and TCF4, the most predominant TCF/LEF factor in the intestine responsible for the recruitment of β-catenin to its target genes, resulting in reduced DNA binding and transcriptional activity at the c-Myc and Cyclin D1 promoters (Ito et al., 2008). These results suggest, at least in part, that the tumour suppressor function of RUNX3 in the intestinal epithelium maybe facilitated through the attenuation of β-catenin/TCF4 factor activity. A follow up study added weight to the view that RUNX3 could physically interact with, and block, the activity of β-catenin/TCF (Ito et al., 2011), although it has also been reported that the same interaction could enhance β-catenin/TCF activity in gastric cell lines (Ju et al., 2014). The tumour-suppressing potential of RUNX3, through its attenuation of Wnt signalling, is not unique to the gastrointestinal tract as RUNX3 reduced β-catenin expression levels and the transactivation potential of β-catenin/TCF4, resulting in reduced proliferation and invasion of glioma cells (Sun et al., 2018). Further support for the concept that RUNX3 might negatively regulate β-catenin and act as a tumour suppressor came from examining oncogenic pathways in laryngeal cancer cells. This work showed that the polycomb protein, enhancer of zeste homolog 2 (EZH2), indirectly stimulates β-catenin activity by epigenetically silencing RUNX3 (Lian et al., 2018).

DISCUSSION

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It is clear, from the evidence laid out in the studies above, that interactions between RUNX factors and Wnt signalling are relevant to both normal tissue and in cancer settings, and that the consequences of such interactions often depend on the specific context in which these connections occur. The apparently paradoxical functions of RUNX1 in breast cancer may be at least partially explained by their alternative interactions with the Wnt signalling pathway in different subtypes (Chimge et al., 2017). In studies relating to the role of RUNX2 in cancer, it has been shown that the oncogenic functions of the protein in both osteosarcomas and breast cancer are related to the regulation of RUNX2 by the Wnt pathway and reciprocal modulation of the Wnt pathway by RUNX2. There is evidence from several studies to suggest that RUNX3 attenuates the function of the Wnt pathway in some gastric and intestinal cancers.

Knowledge of the Wnt pathway and its modulators is essential in aiding the discovery of new ways to target cancer, especially since the canonical Wnt/β-catenin pathway is seen as such a promising target in cancer therapy. As outlined above, the RUNX proteins are key modulators and influencers of the downstream pathways and the phenotypic impact of Wnt signalling, and specific targeting of these RUNX/Wnt interactions may be a more elegant approach to therapy. β-Catenin itself is classified as a difficult-to-drug and yet-to-be-drugged target in cancer and inhibition of this protein could potentially lead to unpleasant side effects in patients (Cheng et al., 2019; Cui et al., 2018). It could, however, be possible to modulate canonical Wnt pathway activation by targeting the RUNX proteins. It is exciting that small molecule inhibitors against RUNX1 and RUNX2 have shown promise for treating some cancer types in which RUNX function drives pro-oncogenic effects, although their effects on the Wnt/β-catenin pathway were not specifically investigated (Bushweller, 2019; Illendula et al., 2016; Kim et al., 2017). However, it should be noted that, depending on context and tumour type, upregulation of RUNX rather than inhibition may augment approaches to therapy (Speidel et al., 2017). Nonetheless, this information offers an additional insight into one of the ways that oncogenic β-catenin signalling can be modulated in cancer, and may be vital for the development of targeted therapies.

ACKNOWLEDGMENTS

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This review is dedicated to our colleague and long-time friend Professor Jim Neil who was a major contributor and ally to the RUNX field. The authors would like to sincerely apologise to colleagues who have contributed to such an immense literature but whose elegant work we have not cited due to space limitations. We thank Kirsteen Campbell for critical reading of the manuscript, and Christopher Boyle for assistance with Figure 1.

K.S. is funded by Breast Cancer Now (2016NovPHD859); K.B. is funded by Cancer Research UK (C596/A17196).

FIGURES

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Fig. 1D Wnt pathway and RUNX gene alterations in a pan-cancer analysis of the TCGA database. Top 20 cancer types where alterations in Wnt pathway components (A) or all three RUNX genes (B) are most frequently observed, including matched information on the percentage of samples with reciprocal RUNX/Wnt alterations. Shown in bold are the cancer types that appear in both top 20 lists. (C) The top 20 cancer types with RUNX alterations were each analysed for their percentage alteration of individual RUNX genes (RUNX1, blue; RUNX2, orange; RUNX3, green). Note that alterations of the RUNX genes are not always mutually exclusive and there can be cooccurrence in RUNX alterations (as demonstrated in ). Therefore, the maximum alteration frequency (%) displayed in Figure 1C is not necessarily representative of the total RUNX alteration frequency in Figures 1A and 1B, particularly in cancer types where more than one RUNX family member is altered. (D) A co-occurrence matrix was generated to observe co-occurrence between alterations in RUNX genes and listed Wnt pathway components in a pan-cancer analysis. The heat map, showing the log2 odds ratio, quantifies how strongly the presence or absence of alterations in gene X are associated with the presence or absence of alterations in gene Y. The heat maps are displayed only in the boxes of gene matches where the co-occurrence or mutual exclusivity was shown to be significant using the q-values (Derived from Benjamini–Hochberg false discovery rate [FDR] correction procedure). Wnt pathway components were selected for these analyses from the Wnt homepage, created by the Nusse Lab (http://web.stanford.edu/group/nusselab/cgi-bin/wnt/). All data for this figure was obtained through cBioPortal for Cancer Genomics (https://www.cbioportal.org/) using the TCGA PanCancer Atlas Studies (Cerami et al., 2012; Gao et al., 2013).
Fig. 2. Overview of RUNX/Wnt pathway interactions and co-regulation. A summary of the interaction between RUNX and Wnt signalling showing that RUNX can transcriptionally regulate a number of Wnt pathway genes whilst the RUNX genes themselves are subject to regulation by β-catenin, the transcriptional mediator of the canonical Wnt pathway. Also highlighted is the cooperation between both β-catenin and RUNX in the regulation of Wnt target genes. The kinase GSK3β is an important component of the β-catenin destruction complex but can also phosphorylate RUNX and inhibit function.

TABLES

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Table 1.

Overlapping incidence of RUNX gene and Wnt pathway alterations in cancer

Cancer typeAlteration frequency (%)
RUNXWntRUNX + WntRUNX/Wnt analysisRUNX/Wnt overlap
Colorectal adenocarcinoma6.48389.483.336.07
Endometrial carcinoma9.972.3582.2572.879.38
Oesophagogastric adenocarcinoma11.8771.683.4773.549.93
Melanoma8.7870.9579.7372.756.98
Non-small cell lung cancer5.5166.7672.2767.94.37
Hepatocellular carcinoma4.0765.8569.9266.673.25
Ovarian epithelial tumour6.6865.2471.9266.785.14
Bladder urothelial carcinoma8.5263.9972.5165.696.82
Cervical squamous cell carcinoma5.5854.5860.1656.973.19
Head and neck squamous cell carcinoma5.1654.359.4656.213.25
Sarcoma6.6752.1658.8352.945.89
Invasive breast carcinoma8.1250.9259.0454.154.89
Mature B-cell neoplasms6.2547.9254.1747.926.25
Cervical adenocarcinoma4.3543.4847.8345.652.18
Pancreatic adenocarcinoma3.838.0441.8438.593.25
Adrenocortical carcinoma3.332.9736.2734.072.2
Cholangiocarcinoma5.5630.5636.1233.332.79

The cancer types that appeared in both top 20 lists for RUNX and select Wnt pathway alterations in Figures 1A and 1B were further an-alysed for overlapping occurrence of Wnt pathway and RUNX alterations. RUNX refers to alteration in any of the three genes (RUNX1, RUNX2, RUNX3). When the incidence of RUNX and Wnt pathway alterations were analysed individually, the total percentage of these was higher than the alteration frequency obtained by analysing the frequency of RUNX and Wnt pathway alterations simultaneously, in-dicating that these alterations co-occur (and supporting the data shown in Fig. 1D). The percentage overlap in Wnt pathway and RUNX alterations was obtained for each of the analysed cancer types by calculating the difference between the RUNX/Wnt simultaneous analy-sis alteration frequency and the individual RUNX and Wnt pathway alteration frequencies added together. The same Wnt pathway com-ponents analysed in Figure 1, selected from the Wnt homepage (http://web.stanford.edu/group/nusselab/cgi-bin/wnt/), were also used for this analysis. Data was mined from cBioPortal for Cancer Genomics using the TCGA PanCancer Atlas Studies (https://www.cbioportal.org/) (Cerami et al., 2012; Gao et al., 2013).

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Article

Minireview

Mol. Cells 2020; 43(2): 188-197

Published online February 29, 2020 https://doi.org/10.14348/molcells.2019.0310

Copyright © The Korean Society for Molecular and Cellular Biology.

Complex Interplay between the RUNX Transcription Factors and Wnt/β-Catenin Pathway in Cancer: A Tango in the Night

Kerri Sweeney1 , Ewan R. Cameron2,* , and Karen Blyth1,3,*

1CRUK Beatson Institute, Garscube Estate, Glasgow G61 1BD, UK, 2Glasgow Veterinary School, University of Glasgow, Glasgow G61 1QH, UK, 3Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK

Correspondence to:Ewan.Cameron@glasgow.ac.uk (ERC); Karen.Blyth@glasgow.ac.uk (KB)

Received: December 12, 2019; Accepted: December 19, 2019

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Cells are designed to be sensitive to a myriad of external cues so they can fulfil their individual destiny as part of the greater whole. A number of well-characterised signalling pathways dictate the cell’s response to the external environment and incoming messages. In healthy, well-ordered homeostatic systems these signals are tightly controlled and kept in balance. However, given their powerful control over cell fate, these pathways, and the transcriptional machinery they orchestrate, are frequently hijacked during the development of neoplastic disease. A prime example is the Wnt signalling pathway that can be modulated by a variety of ligands and inhibitors, ultimately exerting its effects through the β-catenin transcription factor and its downstream target genes. Here we focus on the interplay between the three-member family of RUNX transcription factors with the Wnt pathway and how together they can influence cell behaviour and contribute to cancer development. In a recurring theme with other signalling systems, the RUNX genes and the Wnt pathway appear to operate within a series of feedback loops. RUNX genes are capable of directly and indirectly regulating different elements of the Wnt pathway to either strengthen or inhibit the signal. Equally, β-catenin and its transcriptional co-factors can control RUNX gene expression and together they can collaborate to regulate a large number of third party co-target genes.

Keywords: cancer, RUNX1, RUNX2, RUNX3, Wnt, β-catenin

INTRODUCTION

Cells consult their extracellular environment, and the growth-regulating signals within it, during a discrete window of time in G1 phase of the cell cycle. Once cells have moved through this window, they proceed through S, G2, and M phases. However, if growth factors are removed before a specific time point, cells will fail to proceed toward S phase, and instead remain in G1 or revert to G0 phase (Pardee, 1974). This total dependence on extracellular signals, followed by entrance in late G1 into a state of relative independence, indicates that an important decision must be made before the end of G1. Precisely at this point, a cell must ‘make up its mind’ whether it will remain in G1, retreat from the active cycle into G0, or advance into late G1 and S phase. This critical decision is made at the restriction point or R-point (Malumbres and Barbacid, 2001; Pardee, 1974; Weinberg, 2014).

Time-lapse microscopy of asynchronously cycling Swiss 3T3 cells showed that cycling cells are sensitive to serum withdrawal for only the first 3 to 4 h after mitosis, implying that the R-point is within this interval (Zetterberg and Larsson, 1985). Subsequent studies revealed that the R-point occurs 3 to 4 h after mitogenic stimulation in most mammalian cells (Zetterberg et al., 1995). The concept of the R-point heralded the subsequent discovery of the cell-cycle engine (Nurse, 2000; Pardee, 1974; Sherr and Roberts, 1999). In addition, the R-point is deregulated in most cancer cells (Pardee, 1974; Weinberg, 2014). Therefore, understanding how cells make a fate decision at the R-point should provide insight into how the cell cycle is controlled and how tumors develop (Blagosklonny, 2006).

The DNA-binding transcription factor RUNX3, which plays pivotal roles in lineage determination, defends against oncogenic K-RAS–induced tumorigenesis (Ito et al., 2015). Deletion of Runx3 in mouse lung results in development of lung adenomas and accelerates oncogenic K-Ras–induced progression into adenocarcinomas (Lee et al., 2013). In mouse embryonic fibroblasts, Runx3 deletion perturbs the R-point, leading to transformation (Chi et al., 2017). Recent work showed that RUNX3 functions as a pioneer factor that plays key roles in R-point–associated induction of immediate early genes, including p21Waf/Cip (hereafter p21) and p19ARF (p14ARF in human, hereafter ARF). In this review, we summarize how RUNX3 contributes to the R-point decision in collaboration with histone modifiers, chromatin-remodeling complexes, the basal transcriptional machinery, and Polycomb group (PcG) proteins.

CHROMATIN DYNAMICS ASSOCIATED WITH R-POINT REGULATION

When extracellular mitogenic signaling is maintained up to the R-point, transcription of R-point–associated target genes is activated (Chi et al., 2017). For a silent gene to be induced, the chromatin structure of its chromosomal locus must be opened. Chromatin structures and functions are modulated by covalent modification of specific residues within the amino-terminal tails of histones; the unique combination of modifications has been described as the histone code (Mills, 2010). Trithorax group (TrxG) proteins establish histone modifications that activate transcription, whereas PcG proteins establish histone modifications that repress transcription. TrxG proteins consist of two categories: histone modifiers (Strahl and Allis, 2000) and nucleosome remodelers (Vignali et al., 2000). TrxG histone modifiers include the mixed-lineage leukemia (MLL) protein, which methylates histone H3 at lysine 4 (H3K4-me), a histone mark that favors transcriptional activation. Nucleosome remodelers of TrxG complex contain SWI/SNF complex, which facilitate the binding of transcription factors and basal transcription machinery (Imbalzano et al., 1994). PcG complexes include two categories: Polycomb repressor complexes 1 and 2 (PRC1 and PRC2). The PRC2 complex contains Enhancer of Zeste Homolog 2 (EZH2), which trimethylates histone H3 at lysine 27 (H3K27-me), a characteristic of inactive chromatin (Cao et al., 2002).

Gain of PcG and loss of TrxG is a common theme in human cancer, indicating that PcG and TrxG are involved in regulation of tumor suppressors: PcG suppresses and TrxG activates tumor suppressors. ARF, which induces cell-cycle arrest and apoptosis by facilitating p53 activity in response to aberrant oncogene activation (Efeyan and Serrano, 2007; Kamijo et al., 1997; Palmero et al., 1998), is regulated by PcG and TrxG. During normal proliferation, PcG complexes (PRC1 and PRC2) and histone deacetylases (HDACs) bind the ARF locus, thereby inhibiting senescence. In response to oncogenic RAS, TrxG-mediated chromatin dynamics override PcG-mediated repression, thereby inducing ARF/p53-mediated senescence (Mills, 2010).

ENTERING INTO THE R-POINT AND ACTIVATION OF R-POINT–ASSOCIATED GENES

Soon after mitogenic stimulation (within 1 h after stimulation), histone H4 and RUNX are acetylated by p300 acetyltransferase. BRD2 contains two bromodomains (BD1 and BD2), and each bromodomain interacts with a distinct protein: BD1 interacts with acetylated RUNX3, whereas BD2 interacts with acetylated histone H4. The p300–RUNX3–BRD2– histone complex is formed 1 to 2 h after serum stimulation, and binds to the promoters of the genes encoding p21 and ARF (Lee et al., 2019a). The complex dissociates 4 h later (Lee et al., 2019a). These observations suggest that a large complex containing RUNX3, BRD2, p300, and histone forms at the promoters of p21 and ARF at the R-point; within this complex, BRD2 grips both RUNX3 and histone through its two BDs. A schematic diagram of the complex formed at target loci soon after serum stimulation is shown in Figure 1.

BRD2 participates in multiprotein transcription complexes such as Mediator, recruits the SWI/SNF chromatin-remodeling complex (Denis et al., 2006), and allows RNA polymerase II to transcribe through the nucleosome (LeRoy et al., 2008). Interestingly, TAF1 and TBP form a complex with RUNX3 and BRD2 1 h after serum stimulation (Fig. 1). Similarly, MLL1/5 (activating histone modifiers) and the components of the SWI/SNF complex, Brg-1 and BAF-155, interact with RUNX3 and BRD2 simultaneously 1 to 2 h after serum stimulation, and subsequently dissociate (Fig. 1). These results demonstrate that the p300–RUNX3–BRD2–histone complex interacts with MLL1/5 as well as the SWI/SNF and TFIID complexes before the R-point.

ARF is a target of RUNX3 (Lee et al., 2013) that is critical for the life and death of cells; thus regulation of its expression could represent the R-point decision. Lee et al. (2019a) showed that MLL1/5, SWI/SNF, and TFIID are recruited to the ARF promoter locus, but not when the RUNX3 binding site is deleted. Consistent with this, MLL1/5, SWI/SNF, and TFIID are not recruited to the ARF promoter in H460 cells, which do not express RUNX3 but are recruited after ectopic expression of RUNX3. These results demonstrated that the MLL1/5, SWI/ SNF, and TFIID complexes are recruited to the ARF promoter, and that their recruitment is guided by RUNX3. The large RUNX3-containing complex formed before the R-point has been designated as the R-point–associated RUNX3-containing activator complex (Rpa-RX3-AC) (Fig. 1).

RUNX3 IS A PIONEER FACTOR OF THE R-POINT

Interaction between Wnt and RUNX1 activity was reported over 20 years ago when it was shown that the β-catenin co-factor lymphoid enhancer factor 1 (LEF1) enhanced RUNX1 binding to chromatin and potentiated transcriptional activity of the T-cell receptor alpha (TCRα) enhancer (Mayall et al., 1997). Subsequently the mutual interdependence of these pathways has been described in systems as diverse as haematopoietic stem cells and ovaries, with RUNX1 capable of affecting the Wnt pathway at several discreet components of the pathway (Cheng et al., 2011; Friedman, 2009; Naillat et al., 2015; Wu et al., 2012).

The role of RUNX1 in leukaemia has been studied in the context of Wnt signalling whereby β-catenin is associated with the ability of leukaemia stem cells to self-renew. Treatment of haematopoietic progenitor cells with purified Wnt3a ligand increased the transcription of ETO and RUNX1 in addition to enhancing their spatial proximity. These events could precipitate translocation events between RUNX1 and ETO genes, resulting in the formation of the RUNX1-ETO fusion protein, which is a common mutation found in AML patients (Ugarte et al., 2015). Following from this work, it was found that, through Wnt3a treatment of leukaemia-derived cell lines and CD34+ progenitor cells, the distal P1 promoter of RUNX1 harboured a T-cell factor/lymphoid enhancer factor (TCF/LEF) binding site identifying this isoform as a bona fide target of β-catenin (Medina et al., 2016). It can be hypothesised that dysregulation of the Wnt pathway in haematopoietic progenitor cells leads to increased P1-Runx1 and ETO transcription and fusion, facilitating the development of leukaemia.

A number of studies have noted that RUNX1 mutation and putative loss of function is restricted to the ER+ subset of breast cancers (Banerji et al., 2012; Ellis et al., 2012). In an elegant study Chimge et al. (2016) provided one possible rationale for this observation when they showed that RUNX1 could act to block oestrogen-mediated inhibition of AXIN1 and that loss of RUNX1 could therefore release the oncogenic effects of oestrogen through stabilization of β-catenin. Conversely, in other cell lineages (for example, bone marrow), RUNX1 has been shown to potentiate β-catenin activity through other mechanisms, including the upregulation of activating Wnt ligands (Luo et al., 2019). However, studies in mouse skin demonstrated that the effects of RUNX1 on the Wnt signalling pathway are lineage dependent (Scheitz and Tumbar, 2013). As noted, reciprocal regulation between RUNX1 and β-catenin has been identified in a number of systems and may be expected given the complexity of gene regulation and cross talk between key regulators of survival, differentiation and proliferation. A more unique connection was reported by Jain et al. (2018) who suggested that RUNX1-induced changes in the structure of the cell membrane may render cells more sensitive to extracellular Wnt signals.

RUNX1 was found to be upregulated in colorectal cancer and this overexpression was linked to poorer survival in patients, as well as metastasis and induction of epithelial-to-mesenchymal transition (EMT) in colorectal cancer cells (Li et al., 2019). This aggressive phenotype was caused by RUNX1 activating the Wnt pathway via direct interaction with β-catenin, and interactions with the enhancer and promoter regions of KIT to promote its transcription and enhance Wnt/β-catenin signalling. Conversely, Runx1 deficiency in the mouse intestine was sufficient for tumour formation and significantly enhanced tumorigenesis in an ApcMin model of intestinal tumorigenesis (Fijneman et al., 2012). Gene expression analysis of colons from Runx1 KO mice revealed upregulations in genes previously described as transcriptional targets of β-catenin; Angiogenin4 (Ang4) and serine peptidase inhibitor, Kazal type 4 (Spink4); both of which were also previously found to be upregulated in Apc–/– colon cells (Andreu et al., 2008; Fijneman et al., 2012; Gregorieff et al., 2009). This potentially provides a mechanism by which Runx1 loss in the colon results in the expansion of stem cell populations and subsequent susceptibility to tumour initiation. The role of RUNX1/Wnt interactions in solid cancers may also extend to other major tumour types, for example high RUNX1 expression was predictive of a poor prognosis in clear cell renal cell carcinoma while Wnt signalling pathway was significantly enriched in tissues with high RUNX1 expression (Fu et al., 2019).

Interactions between RUNX2 and the Wnt pathway

Bone is a highly dynamic tissue and both the Wnt signalling pathway and RUNX2 are integral to its formation and homeostatic control. As such, the bone field has been a rich source for studying the intricate relationship between these players. Runx2 is itself a downstream target of the canonical Wnt pathway (Fig. 2) and β-catenin/TCF activate Runx2 expression through a TCF binding site in the proximal promoter (Gaur et al., 2005), or through protein-protein interactions on Runx2 enhancer elements (Kawane et al., 2014). These studies reveal direct linkage between the osteogenic activity of the Wnt/β-catenin pathways and the key transcription factor mediating osteoblastic differentiation and bone development. Wnt induction of Runx2 is not restricted to osteoblasts and direct regulation by β-catenin/LEF1 has also been shown in chondrocytes (Dong et al., 2006). The importance of this applies to other systems, including pathophysiological processes inducing the calcification of vascular smooth muscle cells, where two other TCF binding sites were identified in the Runx2 proximal promoter (Cai et al., 2016).

Reciprocal regulation of major signalling pathways is a common theme with the Runx genes and in turn RUNX2 has been shown to regulate a variety of Wnt ligands (Qin et al., 2019), Wnt inhibitors (James et al., 2006; Mendoza-Villanueva et al., 2011; Perez-Campo et al., 2016) and TCF/LEF co-activators (Hoeppner et al., 2009; Mikasa et al., 2011), and in this way modulate the strength and specificity of the canonical Wnt pathway (Fig. 2). Although Wnt signalling and RUNX2 can clearly collaborate in bone development, it has been shown that enforced expression of RUNX2 in osteoblast cells can reduce levels of β-catenin and inhibit its transcriptional activity, perhaps to ensure fine tuning in the control of terminal differentiation (Haxaire et al., 2016). Intriguingly, GSK3β, the central player of the β-catenin destruction complex, also phosphorylates and negatively regulates RUNX2, suggesting a coordinated approach to the regulation of these transcription factors (Kugimiya et al., 2007).

In addition to their ability to regulate each other, β-catenin and RUNX2 also collaborate in the regulation of common target genes (Fig. 2). RUNX2 and canonical Wnt interact to regulate FGF18 (Reinhold and Naski, 2007) and Osteocalcin (Tang et al., 2009), whilst in other systems RUNX2 has been shown to be a fully paid-up member of the Wnt enhanceosome, the transcription complex that brings together TCFs and β β-catenin/LEF can block RUNX2 transcriptional activation by interacting directly with the DNA binding domain of RUNX2 (Kahler and Westendorf, 2003).

Wnt signalling has been implicated in different aspects of cancer development and progression. The role of this pathway in stem cell biology and tumour initiating cells is one area of intense interest. Our own work has shown that Runx2 expression is upregulated by Wnt3a; enriched in cells with the capacity to form mammospheres; and is required for mammary gland reconstitution in vivo (Ferrari et al., 2015). Importantly, RUNX2 was upregulated in Wnt-driven mammary tumours, suggesting that Runx2 was a Wnt target that could participate in both stem cell activity and tumour growth (Ferrari et al., 2015). The relationship between Wnt signalling and Runx genes in stem cells may extend to other lineages and may be ancestral as studies in C. elegans have revealed that the RUNX homologue RNT-1 acts on Wnt signalling through the suppression of POP-1 (TCF/LEF) to ensure stem cell renewal via symmetrical proliferation (van der Horst et al., 2019). At later stages of tumour development, RUNX2 has been associated with a more invasive phenotype of mammary cancer, an effect that may require co-activation of the Wnt pathway (Chimge et al., 2011). Conversely, RUNX2-induced inhibition of Wnt signalling in bone tissue may be involved in preparing the tumour site for colonisation (Mendoza-Villanueva et al., 2011).

Attenuation of Wnt signalling by RUNX3 in cancer

A body of work has implicated RUNX3 as a tumour suppressor in the gastrointestinal tract as well as other cancer lineages, and a number of potential mechanisms have been proposed to explain this property. In this context RUNX3 was reported to form a complex with β-catenin and TCF4, the most predominant TCF/LEF factor in the intestine responsible for the recruitment of β-catenin to its target genes, resulting in reduced DNA binding and transcriptional activity at the c-Myc and Cyclin D1 promoters (Ito et al., 2008). These results suggest, at least in part, that the tumour suppressor function of RUNX3 in the intestinal epithelium maybe facilitated through the attenuation of β-catenin/TCF4 factor activity. A follow up study added weight to the view that RUNX3 could physically interact with, and block, the activity of β-catenin/TCF (Ito et al., 2011), although it has also been reported that the same interaction could enhance β-catenin/TCF activity in gastric cell lines (Ju et al., 2014). The tumour-suppressing potential of RUNX3, through its attenuation of Wnt signalling, is not unique to the gastrointestinal tract as RUNX3 reduced β-catenin expression levels and the transactivation potential of β-catenin/TCF4, resulting in reduced proliferation and invasion of glioma cells (Sun et al., 2018). Further support for the concept that RUNX3 might negatively regulate β-catenin and act as a tumour suppressor came from examining oncogenic pathways in laryngeal cancer cells. This work showed that the polycomb protein, enhancer of zeste homolog 2 (EZH2), indirectly stimulates β-catenin activity by epigenetically silencing RUNX3 (Lian et al., 2018).

DISCUSSION

It is clear, from the evidence laid out in the studies above, that interactions between RUNX factors and Wnt signalling are relevant to both normal tissue and in cancer settings, and that the consequences of such interactions often depend on the specific context in which these connections occur. The apparently paradoxical functions of RUNX1 in breast cancer may be at least partially explained by their alternative interactions with the Wnt signalling pathway in different subtypes (Chimge et al., 2017). In studies relating to the role of RUNX2 in cancer, it has been shown that the oncogenic functions of the protein in both osteosarcomas and breast cancer are related to the regulation of RUNX2 by the Wnt pathway and reciprocal modulation of the Wnt pathway by RUNX2. There is evidence from several studies to suggest that RUNX3 attenuates the function of the Wnt pathway in some gastric and intestinal cancers.

Knowledge of the Wnt pathway and its modulators is essential in aiding the discovery of new ways to target cancer, especially since the canonical Wnt/β-catenin pathway is seen as such a promising target in cancer therapy. As outlined above, the RUNX proteins are key modulators and influencers of the downstream pathways and the phenotypic impact of Wnt signalling, and specific targeting of these RUNX/Wnt interactions may be a more elegant approach to therapy. β-Catenin itself is classified as a difficult-to-drug and yet-to-be-drugged target in cancer and inhibition of this protein could potentially lead to unpleasant side effects in patients (Cheng et al., 2019; Cui et al., 2018). It could, however, be possible to modulate canonical Wnt pathway activation by targeting the RUNX proteins. It is exciting that small molecule inhibitors against RUNX1 and RUNX2 have shown promise for treating some cancer types in which RUNX function drives pro-oncogenic effects, although their effects on the Wnt/β-catenin pathway were not specifically investigated (Bushweller, 2019; Illendula et al., 2016; Kim et al., 2017). However, it should be noted that, depending on context and tumour type, upregulation of RUNX rather than inhibition may augment approaches to therapy (Speidel et al., 2017). Nonetheless, this information offers an additional insight into one of the ways that oncogenic β-catenin signalling can be modulated in cancer, and may be vital for the development of targeted therapies.

ACKNOWLEDGMENTS

This review is dedicated to our colleague and long-time friend Professor Jim Neil who was a major contributor and ally to the RUNX field. The authors would like to sincerely apologise to colleagues who have contributed to such an immense literature but whose elegant work we have not cited due to space limitations. We thank Kirsteen Campbell for critical reading of the manuscript, and Christopher Boyle for assistance with Figure 1.

K.S. is funded by Breast Cancer Now (2016NovPHD859); K.B. is funded by Cancer Research UK (C596/A17196).

Disclosure

The authors have no potential conflicts of interest to disclose.

Figures

Go to
Fig. 1DWnt pathway and RUNX gene alterations in a pan-cancer analysis of the TCGA database. Top 20 cancer types where alterations in Wnt pathway components (A) or all three RUNX genes (B) are most frequently observed, including matched information on the percentage of samples with reciprocal RUNX/Wnt alterations. Shown in bold are the cancer types that appear in both top 20 lists. (C) The top 20 cancer types with RUNX alterations were each analysed for their percentage alteration of individual RUNX genes (RUNX1, blue; RUNX2, orange; RUNX3, green). Note that alterations of the RUNX genes are not always mutually exclusive and there can be cooccurrence in RUNX alterations (as demonstrated in ). Therefore, the maximum alteration frequency (%) displayed in Figure 1C is not necessarily representative of the total RUNX alteration frequency in Figures 1A and 1B, particularly in cancer types where more than one RUNX family member is altered. (D) A co-occurrence matrix was generated to observe co-occurrence between alterations in RUNX genes and listed Wnt pathway components in a pan-cancer analysis. The heat map, showing the log2 odds ratio, quantifies how strongly the presence or absence of alterations in gene X are associated with the presence or absence of alterations in gene Y. The heat maps are displayed only in the boxes of gene matches where the co-occurrence or mutual exclusivity was shown to be significant using the q-values (Derived from Benjamini–Hochberg false discovery rate [FDR] correction procedure). Wnt pathway components were selected for these analyses from the Wnt homepage, created by the Nusse Lab (http://web.stanford.edu/group/nusselab/cgi-bin/wnt/). All data for this figure was obtained through cBioPortal for Cancer Genomics (https://www.cbioportal.org/) using the TCGA PanCancer Atlas Studies (Cerami et al., 2012; Gao et al., 2013).
Fig. 2.Overview of RUNX/Wnt pathway interactions and co-regulation. A summary of the interaction between RUNX and Wnt signalling showing that RUNX can transcriptionally regulate a number of Wnt pathway genes whilst the RUNX genes themselves are subject to regulation by β-catenin, the transcriptional mediator of the canonical Wnt pathway. Also highlighted is the cooperation between both β-catenin and RUNX in the regulation of Wnt target genes. The kinase GSK3β is an important component of the β-catenin destruction complex but can also phosphorylate RUNX and inhibit function.

Tables

Overlapping incidence of RUNX gene and Wnt pathway alterations in cancer

Cancer type Alteration frequency (%)
RUNX Wnt RUNX + Wnt RUNX/Wnt analysis RUNX/Wnt overlap
Colorectal adenocarcinoma 6.4 83 89.4 83.33 6.07
Endometrial carcinoma 9.9 72.35 82.25 72.87 9.38
Oesophagogastric adenocarcinoma 11.87 71.6 83.47 73.54 9.93
Melanoma 8.78 70.95 79.73 72.75 6.98
Non-small cell lung cancer 5.51 66.76 72.27 67.9 4.37
Hepatocellular carcinoma 4.07 65.85 69.92 66.67 3.25
Ovarian epithelial tumour 6.68 65.24 71.92 66.78 5.14
Bladder urothelial carcinoma 8.52 63.99 72.51 65.69 6.82
Cervical squamous cell carcinoma 5.58 54.58 60.16 56.97 3.19
Head and neck squamous cell carcinoma 5.16 54.3 59.46 56.21 3.25
Sarcoma 6.67 52.16 58.83 52.94 5.89
Invasive breast carcinoma 8.12 50.92 59.04 54.15 4.89
Mature B-cell neoplasms 6.25 47.92 54.17 47.92 6.25
Cervical adenocarcinoma 4.35 43.48 47.83 45.65 2.18
Pancreatic adenocarcinoma 3.8 38.04 41.84 38.59 3.25
Adrenocortical carcinoma 3.3 32.97 36.27 34.07 2.2
Cholangiocarcinoma 5.56 30.56 36.12 33.33 2.79

Fig 1.

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Figure 1.Wnt pathway and RUNX gene alterations in a pan-cancer analysis of the TCGA database. Top 20 cancer types where alterations in Wnt pathway components (A) or all three RUNX genes (B) are most frequently observed, including matched information on the percentage of samples with reciprocal RUNX/Wnt alterations. Shown in bold are the cancer types that appear in both top 20 lists. (C) The top 20 cancer types with RUNX alterations were each analysed for their percentage alteration of individual RUNX genes (RUNX1, blue; RUNX2, orange; RUNX3, green). Note that alterations of the RUNX genes are not always mutually exclusive and there can be cooccurrence in RUNX alterations (as demonstrated in Fig. 1D). Therefore, the maximum alteration frequency (%) displayed in Figure 1C is not necessarily representative of the total RUNX alteration frequency in Figures 1A and 1B, particularly in cancer types where more than one RUNX family member is altered. (D) A co-occurrence matrix was generated to observe co-occurrence between alterations in RUNX genes and listed Wnt pathway components in a pan-cancer analysis. The heat map, showing the log2 odds ratio, quantifies how strongly the presence or absence of alterations in gene X are associated with the presence or absence of alterations in gene Y. The heat maps are displayed only in the boxes of gene matches where the co-occurrence or mutual exclusivity was shown to be significant using the q-values (Derived from Benjamini–Hochberg false discovery rate [FDR] correction procedure). Wnt pathway components were selected for these analyses from the Wnt homepage, created by the Nusse Lab (http://web.stanford.edu/group/nusselab/cgi-bin/wnt/). All data for this figure was obtained through cBioPortal for Cancer Genomics (https://www.cbioportal.org/) using the TCGA PanCancer Atlas Studies (Cerami et al., 2012; Gao et al., 2013).
Molecules and Cells 2020; 43: 188-197https://doi.org/10.14348/molcells.2019.0310

Fig 2.

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Figure 2.Overview of RUNX/Wnt pathway interactions and co-regulation. A summary of the interaction between RUNX and Wnt signalling showing that RUNX can transcriptionally regulate a number of Wnt pathway genes whilst the RUNX genes themselves are subject to regulation by β-catenin, the transcriptional mediator of the canonical Wnt pathway. Also highlighted is the cooperation between both β-catenin and RUNX in the regulation of Wnt target genes. The kinase GSK3β is an important component of the β-catenin destruction complex but can also phosphorylate RUNX and inhibit function.
Molecules and Cells 2020; 43: 188-197https://doi.org/10.14348/molcells.2019.0310

. Overlapping incidence of RUNX gene and Wnt pathway alterations in cancer.

Cancer typeAlteration frequency (%)
RUNXWntRUNX + WntRUNX/Wnt analysisRUNX/Wnt overlap
Colorectal adenocarcinoma6.48389.483.336.07
Endometrial carcinoma9.972.3582.2572.879.38
Oesophagogastric adenocarcinoma11.8771.683.4773.549.93
Melanoma8.7870.9579.7372.756.98
Non-small cell lung cancer5.5166.7672.2767.94.37
Hepatocellular carcinoma4.0765.8569.9266.673.25
Ovarian epithelial tumour6.6865.2471.9266.785.14
Bladder urothelial carcinoma8.5263.9972.5165.696.82
Cervical squamous cell carcinoma5.5854.5860.1656.973.19
Head and neck squamous cell carcinoma5.1654.359.4656.213.25
Sarcoma6.6752.1658.8352.945.89
Invasive breast carcinoma8.1250.9259.0454.154.89
Mature B-cell neoplasms6.2547.9254.1747.926.25
Cervical adenocarcinoma4.3543.4847.8345.652.18
Pancreatic adenocarcinoma3.838.0441.8438.593.25
Adrenocortical carcinoma3.332.9736.2734.072.2
Cholangiocarcinoma5.5630.5636.1233.332.79

The cancer types that appeared in both top 20 lists for RUNX and select Wnt pathway alterations in Figures 1A and 1B were further an-alysed for overlapping occurrence of Wnt pathway and RUNX alterations. RUNX refers to alteration in any of the three genes (RUNX1, RUNX2, RUNX3). When the incidence of RUNX and Wnt pathway alterations were analysed individually, the total percentage of these was higher than the alteration frequency obtained by analysing the frequency of RUNX and Wnt pathway alterations simultaneously, in-dicating that these alterations co-occur (and supporting the data shown in Fig. 1D). The percentage overlap in Wnt pathway and RUNX alterations was obtained for each of the analysed cancer types by calculating the difference between the RUNX/Wnt simultaneous analy-sis alteration frequency and the individual RUNX and Wnt pathway alteration frequencies added together. The same Wnt pathway com-ponents analysed in Figure 1, selected from the Wnt homepage (http://web.stanford.edu/group/nusselab/cgi-bin/wnt/), were also used for this analysis. Data was mined from cBioPortal for Cancer Genomics using the TCGA PanCancer Atlas Studies (https://www.cbioportal.org/) (Cerami et al., 2012; Gao et al., 2013)..

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Mol. Cells
May 31, 2023 Vol.46 No.5, pp. 259~328
COVER PICTURE
The alpha-helices in the lamin filaments are depicted as coils, with different subdomains distinguished by various colors. Coil 1a is represented by magenta, coil 1b by yellow, L2 by green, coil 2a by white, coil 2b by brown, stutter by cyan, coil 2c by dark blue, and the lamin Ig-like domain by grey. In the background, cells are displayed, with the cytosol depicted in green and the nucleus in blue (Ahn et al., pp. 309-318).
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