Mol. Cells 2020; 43(2): 188~197  https://doi.org/10.14348/molcells.2019.0310
Complex Interplay between the RUNX Transcription Factors and Wnt/β-Catenin Pathway in Cancer: A Tango in the Night
Kerri Sweeney 1, Ewan R. Cameron 2,*, and Karen Blyth 1,3,*
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
Received December 12, 2019; Accepted December 19, 2019.; Published online February 3, 2020.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

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
Fig. 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).
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

Table 1

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

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).


REFERENCES
  1. Akech, J., Wixted, J.J., Bedard, K., van der Deen, M., Hussain, S., Guise, T.A., van Wijnen, A.J., Stein, J.L., Languino, L.R., Altieri, D.C., et al. (2010). Runx2 association with progression of prostate cancer in patients: mechanisms mediating bone osteolysis and osteoblastic metastatic lesions. Oncogene 29, 811-82.
    Pubmed KoreaMed CrossRef
  2. Anastas, J.N., and Moon, R.T. (2013). WNT signalling pathways as thera­peutic targets in cancer. Nat. Rev. Cancer 13, 11-26.
    Pubmed CrossRef
  3. Andreu, P., Peignon, G., Slomianny, C., Taketo, M.M., Colnot, S., Robine, S., Lamarque, D., Laurent-Puig, P., Perret, C., and Romagnolo, B. (2008). A genetic study of the role of the Wnt/beta-catenin signalling in Paneth cell differentiation. Dev. Biol. 324, 288-296.
    Pubmed CrossRef
  4. Araki, K., Osaki, M., Nagahama, Y., Hiramatsu, T., Nakamura, H., Ohgi, S., and Ito, H. (2005). Expression of RUNX3 protein in human lung adeno­carcinoma: implications for tumor progression and prognosis. Cancer Sci. 96, 227-231.
    Pubmed CrossRef
  5. Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K.K., Carter, S.L., Frederick, A.M., Lawrence, M.S., Sivachenko, A.Y., Sougnez, C., Zou, L., et al. (2012). Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405-409.
    Pubmed KoreaMed CrossRef
  6. Barker, N., and Clevers, H. (2006). Mining the Wnt pathway for cancer therapeutics. Nat. Rev. Drug Discov. 5, 997-1014.
    Pubmed CrossRef
  7. Barnes, G.L., Hebert, K.E., Kamal, M., Javed, A., Einhorn, T.A., Lian, J.B., Stein, G.S., and Gerstenfeld, L.C. (2004). Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease. Cancer Res. 64, 4506-4513.
    Pubmed CrossRef
  8. Barnes, G.L., Javed, A., Waller, S.M., Kamal, M.H., Hebert, K.E., Hassan, M.Q., Bellahcene, A., Van Wijnen, A.J., Young, M.F., Lian, J.B., et al. (2003). Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells. Cancer Res. 63, 2631-2637.
    Pubmed
  9. Ben-Ami, O., Friedman, D., Leshkowitz, D., Goldenberg, D., Orlovsky, K., Pencovich, N., Lotem, J., Tanay, A., and Groner, Y. (2013). Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1. Cell Rep. 4, 1131-1143.
    Pubmed CrossRef
  10. Blyth, K., Cameron, E.R., and Neil, J.C. (2005). The RUNX genes: gain or loss of function in cancer. Nat. Rev. Cancer 5, 376-387.
    Pubmed CrossRef
  11. Bocchinfuso, W.P., Hively, W.P., Couse, J.F., Varmus, H.E., and Korach, K.S. (1999). A mouse mammary tumor virus-Wnt-1 transgene induces mam­mary gland hyperplasia and tumorigenesis in mice lacking estrogen receptor-alpha. Cancer Res. 59, 1869-1876.
    Pubmed
  12. Brenner, O., Levanon, D., Negreanu, V., Golubkov, O., Fainaru, O., Woolf, E., and Groner, Y. (2004). Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc. Natl. Acad. Sci. U. S. A. 101, 16016-16021.
    Pubmed KoreaMed CrossRef
  13. Bushweller, J.H. (2019). Targeting transcription factors in cancer - from undruggable to reality. Nat. Rev. Cancer 19, 611-624.
    Pubmed CrossRef
  14. Cai, T., Sun, D., Duan, Y., Wen, P., Dai, C., Yang, J., and He, W. (2016). WNT/beta-catenin signaling promotes VSMCs to osteogenic transdifferentiation and calcification through directly modulating Runx2 gene expression. Exp. Cell Res. 345, 206-217.
    Pubmed CrossRef
  15. (2012). Comprehensive molecular cha­racterization of human colon and rectal cancer. Nature 487, 330-337.
    Pubmed KoreaMed CrossRef
  16. Cerami, E., Gao, J., Dogrusoz, U., Gross, B.E., Sumer, S.O., Aksoy, B.A., Jacobsen, A., Byrne, C.J., Heuer, M.L., Larsson, E., et al. (2012). The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401-404.
    Pubmed KoreaMed CrossRef
  17. Cheng, C.K., Li, L., Cheng, S.H., Ng, K., Chan, N.P., Ip, R.K., Wong, R.S., Shing, M.M., Li, C.K., and Ng, M.H. (2011). Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia. Blood 118, 6638-6648.
    Pubmed CrossRef
  18. Cheng, X., Xu, X., Chen, D., Zhao, F., and Wang, W. (2019). Therapeutic potential of targeting the Wnt/beta-catenin signaling pathway in colorectal cancer. Biomed. Pharmacother. 110, 473-481.
    Pubmed CrossRef
  19. Chimge, N.O., Ahmed-Alnassar, S., and Frenkel, B. (2017). Relationship between RUNX1 and AXIN1 in ER-negative versus ER-positive breast cancer. Cell Cycle 16, 312-318.
    Pubmed KoreaMed CrossRef
  20. Chimge, N.O., Baniwal, S.K., Little, G.H., Chen, Y.B., Kahn, M., Tripathy, D., Borok, Z., and Frenkel, B. (2011). Regulation of breast cancer metastasis by Runx2 and estrogen signaling: the role of SNAI2. Breast Cancer Res. 13, R127.
    Pubmed KoreaMed CrossRef
  21. Chimge, N.O., Little, G.H., Baniwal, S.K., Adisetiyo, H., Xie, Y., Zhang, T., O'Laughlin, A., Liu, Z.Y., Ulrich, P., Martin, A., et al. (2016). RUNX1 prevents oestrogen-mediated AXIN1 suppression and beta-catenin activation in ER-positive breast cancer. Nat. Commun. 7, 10751.
    Pubmed KoreaMed CrossRef
  22. Choi, A., Illendula, A., Pulikkan, J.A., Roderick, J.E., Tesell, J., Yu, J., Hermance, N., Zhu, L.J., Castilla, L.H., Bushweller, J.H., et al. (2017). RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. Blood 130, 1722-1733.
    Pubmed KoreaMed CrossRef
  23. Chuang, L.S., Ito, K., and Ito, Y. (2017). Roles of RUNX in solid tumors. Adv. Exp. Med. Biol. 962, 299-320.
    Pubmed CrossRef
  24. Clements, W.M., Wang, J., Sarnaik, A., Kim, O.J., MacDonald, J., Fenoglio-Preiser, C., Groden, J., and Lowy, A.M. (2002). beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res. 62, 3503-3506.
    Pubmed
  25. Clevers, H. (2000). Axin and hepatocellular carcinomas. Nat. Genet. 24, 206-208.
    Pubmed CrossRef
  26. Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell 127, 469-480.
    Pubmed CrossRef
  27. Cui, C., Zhou, X., Zhang, W., Qu, Y., and Ke, X. (2018). Is beta-catenin a druggable target for cancer therapy? Trends Biochem. Sci. 43, 623-634.
    Pubmed CrossRef
  28. Dalle Carbonare, L., Frigo, A., Francia, G., Davi, M.V., Donatelli, L., Stranieri, C., Brazzarola, P., Zatelli, M.C., Menestrina, F., and Valenti, M.T. (2012). Runx2 mRNA expression in the tissue, serum, and circulating non-hematopoietic cells of patients with thyroid cancer. J. Clin. Endocrinol. Metab. 97, E1249-1256.
    Pubmed CrossRef
  29. De Braekeleer, E., Ferec, C., and De Braekeleer, M. (2009). RUNX1 trans­locations in malignant hemopathies. Anticancer Res. 29, 1031-1037.
    Pubmed
  30. Dey, N., Barwick, B.G., Moreno, C.S., Ordanic-Kodani, M., Chen, Z., Oprea-Ilies, G., Tang, W., Catzavelos, C., Kerstann, K.F., Sledge, G.W. Jr., et al. (2013). Wnt signaling in triple negative breast cancer is associated with metastasis. BMC Cancer 13, 537.
    Pubmed KoreaMed CrossRef
  31. Dong, Y.F., Soung do, Y., Schwarz, E.M., O'Keefe, R.J., and Drissi, H. (2006). Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J. Cell. Physiol. 208, 77-86.
    Pubmed CrossRef
  32. Ellis, M.J., Ding, L., Shen, D., Luo, J., Suman, V.J., Wallis, J.W., Van Tine, B.A., Hoog, J., Goiffon, R.J., Goldstein, T.C., et al. (2012). Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353-360.
    Pubmed KoreaMed CrossRef
  33. Endo, T., Ohta, K., and Kobayashi, T. (2008). Expression and function of Cbfa-1/Runx2 in thyroid papillary carcinoma cells. J. Clin. Endocrinol. Metab. 93, 2409-2412.
    Pubmed CrossRef
  34. Ferrari, N., Riggio, A.I., Mason, S., McDonald, L., King, A., Higgins, T., Rosewell, I., Neil, J.C., Smalley, M.J., Sansom, O.J., et al. (2015). Runx2 contributes to the regenerative potential of the mammary epithelium. Sci. Rep. 5, 15658.
    Pubmed KoreaMed CrossRef
  35. Fiedler, M., Graeb, M., Mieszczanek, J., Rutherford, T.J., Johnson, C.M., and Bienz, M. (2015). An ancient Pygo-dependent Wnt enhanceosome integrated by Chip/LDB-SSDP. eLife 4, e09073.
    Pubmed KoreaMed CrossRef
  36. Fijneman, R.J., Anderson, R.A., Richards, E., Liu, J., Tijssen, M., Meijer, G.A., Anderson, J., Rod, A., O'Sullivan, M.G., Scott, P.M., et al. (2012). Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract. Cancer Sci. 103, 593-599.
    Pubmed KoreaMed CrossRef
  37. Friedman, A.D. (2009). Cell cycle and developmental control of hema­topoiesis by Runx1. J. Cell. Physiol. 219, 520-524.
    Pubmed KoreaMed CrossRef
  38. Fu, Y., Sun, S., Man, X., and Kong, C. (2019). Increased expression of RUNX1 in clear cell renal cell carcinoma predicts poor prognosis. PeerJ 7, e7854.
    Pubmed KoreaMed CrossRef
  39. Gao, J., Aksoy, B.A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S.O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013). Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1.
    Pubmed KoreaMed CrossRef
  40. Gaur, T., Lengner, C.J., Hovhannisyan, H., Bhat, R.A., Bodine, P.V., Komm, B.S., Javed, A., van Wijnen, A.J., Stein, J.L., Stein, G.S., et al. (2005). Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J. Biol. Chem. 280, 33132-331.
    Pubmed CrossRef
  41. Goldsberry, W.N., Londono, A., Randall, T.D., Norian, L.A., and Arend, R.C. (2019). A review of the role of Wnt in cancer immunomodulation. Cancers 11, E771.
    Pubmed KoreaMed CrossRef
  42. Goyama, S., Schibler, J., Cunningham, L., Zhang, Y., Rao, Y., Nishimoto, N., Nakagawa, M., Olsson, A., Wunderlich, M., Link, K.A., et al. (2013). Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. J. Clin. Invest. 123, 3876-3888.
    Pubmed KoreaMed CrossRef
  43. Gregorieff, A., Stange, D.E., Kujala, P., Begthel, H., van den Born, M., Korving, J., Peters, P.J., and Clevers, H. (2009). The ets-domain transcription factor Spdef promotes maturation of goblet and paneth cells in the intestinal epithelium. Gastroenterology 137, 1333-1345.
    Pubmed CrossRef
  44. Grigoryan, T., Wend, P., Klaus, A., and Birchmeier, W. (2008). Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev. 22, 2308-2341.
    Pubmed KoreaMed CrossRef
  45. Haxaire, C., Hay, E., and Geoffroy, V. (2016). Runx2 controls bone resorption through the down-regulation of the Wnt pathway in osteoblasts. Am. J. Pathol. 186, 1598-1609.
    Pubmed CrossRef
  46. Hoeppner, L.H., Secreto, F., Jensen, E.D., Li, X., Kahler, R.A., and Westendorf, J.J. (2009). Runx2 and bone morphogenic protein 2 regulate the ex­pression of an alternative Lef1 transcript during osteoblast maturation. J. Cell. Physiol. 221, 480-489.
    Pubmed KoreaMed CrossRef
  47. Illendula, A., Gilmour, J., Grembecka, J., Tirumala, V.S.S., Boulton, A., Kun­timaddi, A., Schmidt, C., Wang, L., Pulikkan, J.A., Zong, H., et al. (2016). Small molecule inhibitor of CBFbeta-RUNX binding for RUNX transcription factor driven cancers. EBioMedicine 8, 117-131.
    Pubmed KoreaMed CrossRef
  48. Ito, K., Chuang, L.S., Ito, T., Chang, T.L., Fukamachi, H., Salto-Tellez, M., and Ito, Y. (2011). Loss of Runx3 is a key event in inducing precancerous state of the stomach. Gastroenterology 140, 1536-1546.
    Pubmed CrossRef
  49. Ito, K., Lim, A.C., Salto-Tellez, M., Motoda, L., Osato, M., Chuang, L.S., Lee, C.W., Voon, D.C., Koo, J.K., Wang, H., et al. (2008). RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell 14, 226-237.
    Pubmed CrossRef
  50. Ito, K., Liu, Q., Salto-Tellez, M., Yano, T., Tada, K., Ida, H., Huang, C., Shah, N., Inoue, M., Rajnakova, A., et al. (2005). RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization. Cancer Res. 65, 7743-77.
    Pubmed CrossRef
  51. Ito, Y., Bae, S.C., and Chuang, L.S. (2015). The RUNX family: developmental regulators in cancer. Nat. Rev. Cancer 15, 81-95.
    Pubmed CrossRef
  52. Jain, P., Nattakom, M., Holowka, D., Wang, D.H., Thomas Brenna, J., Ku, A.T., Nguyen, H., Ibrahim, S.F., and Tumbar, T. (2018). Runx1 role in epithelial and cancer cell proliferation implicates lipid metabolism and Scd1 and Soat1 activity. Stem Cells 36, 1603-1616.
    Pubmed KoreaMed CrossRef
  53. James, M.J., Jarvinen, E., Wang, X.P., and Thesleff, I. (2006). Different roles of Runx2 during early neural crest-derived bone and tooth development. J. Bone Miner. Res. 21, 1034-1044.
    Pubmed CrossRef
  54. Jarvinen, E., Shimomura-Kuroki, J., Balic, A., Jussila, M., and Thesleff, I. (2018). Mesenchymal Wnt/beta-catenin signaling limits tooth number. Development 145, dev158048.
    Pubmed CrossRef
  55. Ju, X., Ishikawa, T.O., Naka, K., Ito, K., Ito, Y., and Oshima, M. (2014). Con­text-dependent activation of Wnt signaling by tumor suppressor RUNX3 in gastric cancer cells. Cancer Sci. 105, 418-424.
    Pubmed KoreaMed CrossRef
  56. Kahler, R.A., and Westendorf, J.J. (2003). Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter. J. Biol. Chem. 278, 11937-11944.
    Pubmed CrossRef
  57. Kawane, T., Komori, H., Liu, W., Moriishi, T., Miyazaki, T., Mori, M., Matsuo, Y., Takada, Y., Izumi, S., Jiang, Q., et al. (2014). Dlx5 and mef2 regulate a novel runx2 enhancer for osteoblast-specific expression. J. Bone Miner. Res. 29, 1960-1969.
    Pubmed CrossRef
  58. Khramtsov, A.I., Khramtsova, G.F., Tretiakova, M., Huo, D., Olopade, O.I., and Goss, K.H. (2010). Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am. J. Pathol. 176, 2911-2920.
    Pubmed KoreaMed CrossRef
  59. Kim, M.S., Gernapudi, R., Choi, E.Y., Lapidus, R.G., and Passaniti, A. (2017). Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity. Oncotarget 8, 70916-70940.
    Pubmed KoreaMed CrossRef
  60. Kinzler, K.W., Nilbert, M.C., Su, L.K., Vogelstein, B., Bryan, T.M., Levy, D.B., Smith, K.J., Preisinger, A.C., Hedge, P., McKechnie, D., et al. (1991). Identi­fication of FAP locus genes from chromosome 5q21. Science 253, 661-665.
    Pubmed CrossRef
  61. Komori, T., Yagi, H., Nomura, S., Yamaguchi, A., Sasaki, K., Deguchi, K., Shimizu, Y., Bronson, R.T., Gao, Y.H., Inada, M., et al. (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755-764.
    Pubmed CrossRef
  62. Korinek, V., Barker, N., Morin, P.J., van Wichen, D., de Weger, R., Kinzler, K.W., Vogelstein, B., and Clevers, H. (1997). Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 275, 1784-1787.
    Pubmed CrossRef
  63. Kugimiya, F., Kawaguchi, H., Ohba, S., Kawamura, N., Hirata, M., Chikuda, H., Azuma, Y., Woodgett, J.R., Nakamura, K., and Chung, U.I. (2007). GSK-3beta controls osteogenesis through regulating Runx2 activity. PLoS One 2, e837.
    Pubmed KoreaMed CrossRef
  64. Kurek, K.C., Del Mare, S., Salah, Z., Abdeen, S., Sadiq, H., Lee, S.H., Gaudio, E., Zanesi, N., Jones, K.B., DeYoung, B., et al. (2010). Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression. Cancer Res. 70, 5577-5586.
    Pubmed KoreaMed CrossRef
  65. Lee, Y.S., Lee, J.W., Jang, J.W., Chi, X.Z., Kim, J.H., Li, Y.H., Kim, M.K., Kim, D.M., Choi, B.S., Kim, E.G., et al. (2013). Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma. Cancer Cell 24, 603-616.
    Pubmed CrossRef
  66. Levanon, D., Bettoun, D., Harris-Cerruti, C., Woolf, E., Negreanu, V., Eilam, R., Bernstein, Y., Goldenberg, D., Xiao, C., Fliegauf, M., et al. (2002). The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J. 21, 3454-3463.
    Pubmed KoreaMed CrossRef
  67. Li, Q., Lai, Q., He, C., Fang, Y., Yan, Q., Zhang, Y., Wang, X., Gu, C., Wang, Y., Ye, L., et al. (2019). RUNX1 promotes tumour metastasis by activating the Wnt/beta-catenin signalling pathway and EMT in colorectal cancer. J. Exp. Clin. Cancer Res. 38, 334.
    Pubmed KoreaMed CrossRef
  68. Li, Q.L., Ito, K., Sakakura, C., Fukamachi, H., Inoue, K., Chi, X.Z., Lee, K.Y., Nomura, S., Lee, C.W., Han, S.B., et al. (2002). Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109, 113-124.
    Pubmed CrossRef
  69. Li, S., Li, S., Sun, Y., and Li, L. (2014). The expression of beta-catenin in different subtypes of breast cancer and its clinical significance. Tumour Biol. 35, 7693-7698.
    Pubmed CrossRef
  70. Lian, R., Ma, H., Wu, Z., Zhang, G., Jiao, L., Miao, W., Jin, Q., Li, R., Chen, P., Shi, H., et al. (2018). EZH2 promotes cell proliferation by regulating the expression of RUNX3 in laryngeal carcinoma. Mol. Cell. Biochem. 439, 35-43.
    Pubmed CrossRef
  71. Lie-a-ling, M., Mevel, R., Patel, R., Blyth, K., Baena, E., Kouskoff, V., and Lacaud, G. (2020). RUNX1 dosage in development and cancer. Mol. Cells 43, 126-138.
    Pubmed
  72. Lin, S.Y., Xia, W., Wang, J.C., Kwong, K.Y., Spohn, B., Wen, Y., Pestell, R.G., and Hung, M.C. (2000). Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc. Natl. Acad. Sci. U. S. A. 97, 4262-4266.
    Pubmed KoreaMed CrossRef
  73. Lotem, J., Levanon, D., Negreanu, V., Bauer, O., Hantisteanu, S., Dicken, J., and Groner, Y. (2015). Runx3 at the interface of immunity, inflammation and cancer. Biochim. Biophys. Acta 1855, 131-143.
    Pubmed CrossRef
  74. Lotem, J., Levanon, D., Negreanu, V., Bauer, O., Hantisteanu, S., Dicken, J., and Groner, Y. (2017). Runx3 in immunity, inflammation and cancer. Adv. Exp. Med. Biol. 962, 369-393.
    Pubmed CrossRef
  75. Luis, T.C., Ichii, M., Brugman, M.H., Kincade, P., and Staal, F.J. (2012). Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development. Leukemia 26, 414-421.
    Pubmed KoreaMed CrossRef
  76. Luo, Y., Zhang, Y., Miao, G., Zhang, Y., Liu, Y., and Huang, Y. (2019). Runx1 regulates osteogenic differentiation of BMSCs by inhibiting adipogenesis through Wnt/beta-catenin pathway. Arch. Oral Biol. 97, 176-184.
    Pubmed CrossRef
  77. Martin, J.W., Zielenska, M., Stein, G.S., van Wijnen, A.J., and Squire, J.A. (2011). The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma 2011, 282745.
    Pubmed KoreaMed CrossRef
  78. Mayall, T.P., Sheridan, P.L., Montminy, M.R., and Jones, K.A. (1997). Distinct roles for P-CREB and LEF-1 in TCR alpha enhancer assembly and activation on chromatin templates in vitro. Genes Dev. 11, 887-899.
    Pubmed CrossRef
  79. McDonald, L., Ferrari, N., Terry, A., Bell, M., Mohammed, Z.M., Orange, C., Jenkins, A., Muller, W.J., Gusterson, B.A., Neil, J.C., et al. (2014). RUNX2 correlates with subtype-specific breast cancer in a human tissue micro­array, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. Dis. Model. Mech. 7, 525-534.
    Pubmed KoreaMed CrossRef
  80. Medina, M.A., Ugarte, G.D., Vargas, M.F., Avila, M.E., Necunir, D., Elorza, A.A., Gutierrez, S.E., and De Ferrari, G.V. (2016). Alternative RUNX1 promo­ter regulation by wnt/beta-catenin signaling in leukemia cells and human hematopoietic progenitors. J. Cell. Physiol. 231, 1460-1467.
    Pubmed CrossRef
  81. Mendoza-Villanueva, D., Zeef, L., and Shore, P. (2011). Metastatic breast cancer cells inhibit osteoblast differentiation through the Runx2/CBFbeta-dependent expression of the Wnt antagonist, sclerostin. Breast Cancer Res. 13, R106.
    Pubmed KoreaMed CrossRef
  82. Mevel, R., Draper, J.E., Lie-a-Ling, M., Kouskoff, V., and Lacaud, G. (2019). RUNX transcription factors: orchestrators of development. Development 146, dev148296.
    Pubmed CrossRef
  83. Mikasa, M., Rokutanda, S., Komori, H., Ito, K., Tsang, Y.S., Date, Y., Yoshida, C.A., and Komori, T. (2011). Regulation of Tcf7 by Runx2 in chondrocyte maturation and proliferation. J. Bone Miner. Metab. 29, 291-299.
    Pubmed CrossRef
  84. Monteiro, J., Gaspar, C., Richer, W., Franken, P.F., Sacchetti, A., Joosten, R., Idali, A., Brandao, J., Decraene, C., and Fodde, R. (2014). Cancer stemness in Wnt-driven mammary tumorigenesis. Carcinogenesis 35, 2-13.
    Pubmed CrossRef
  85. Naillat, F., Yan, W., Karjalainen, R., Liakhovitskaia, A., Samoylenko, A., Xu, Q., Sun, Z., Shen, B., Medvinsky, A., Quaggin, S., et al. (2015). Identification of the genes regulated by Wnt-4, a critical signal for commitment of the ovary. Exp. Cell Res. 332, 163-178.
    Pubmed CrossRef
  86. Niini, T., Kanerva, J., Vettenranta, K., Saarinen-Pihkala, U.M., and Knuutila, S. (2000). AML1 gene amplification: a novel finding in childhood acute lymphoblastic leukemia. Haematologica 85, 362-366.
    Pubmed
  87. Nishisho, I., Nakamura, Y., Miyoshi, Y., Miki, Y., Ando, H., Horii, A., Koyama, K., Utsunomiya, J., Baba, S., and Hedge, P. (1991). Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665-669.
    Pubmed CrossRef
  88. North, T., Gu, T.L., Stacy, T., Wang, Q., Howard, L., Binder, M., Marin-Padilla, M., and Speck, N.A. (1999). Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development 126, 2563-2575.
    Pubmed
  89. Novellasdemunt, L., Antas, P., and Li, V.S. (2015). Targeting Wnt signaling in colorectal cancer. A review in the theme: cell signaling: proteins, pathways and mechanisms. Am. J. Physiol. Cell Physiol. 309, C511-C521.
    Pubmed KoreaMed CrossRef
  90. Nusse, R., and Varmus, H.E. (1982). Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99-109.
    Pubmed CrossRef
  91. Okuda, T., van Deursen, J., Hiebert, S.W., Grosveld, G., and Downing, J.R. (1996). AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321-330.
    Pubmed CrossRef
  92. Osato, M. (2004). Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 23, 4284-4296.
    Pubmed CrossRef
  93. Osorio, K.M., Lilja, K.C., and Tumbar, T. (2011). Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments. J. Cell Biol. 193, 235-250.
    Pubmed KoreaMed CrossRef
  94. Otto, F., Thornell, A.P., Crompton, T., Denzel, A., Gilmour, K.C., Rosewell, I.R., Stamp, G.W., Beddington, R.S., Mundlos, S., Olsen, B.R., et al. (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765-771.
    Pubmed CrossRef
  95. Owens, T.W., Rogers, R.L., Best, S., Ledger, A., Mooney, A.M., Ferguson, A., Shore, P., Swarbrick, A., Ormandy, C.J., Simpson, P.T., et al. (2014). Runx2 is a novel regulator of mammary epithelial cell fate in development and breast cancer. Cancer Res. 74, 5277-5286.
    Pubmed KoreaMed CrossRef
  96. Perez-Campo, F.M., Santurtun, A., Garcia-Ibarbia, C., Pascual, M.A., Valero, C., Garces, C., Sanudo, C., Zarrabeitia, M.T., and Riancho, J.A. (2016). Osterix and RUNX2 are transcriptional regulators of sclerostin in human bone. Calcif. Tissue Int. 99, 302-309.
    Pubmed CrossRef
  97. Pratap, J., Lian, J.B., Javed, A., Barnes, G.L., van Wijnen, A.J., Stein, J.L., and Stein, G.S. (2006). Regulatory roles of Runx2 in metastatic tumor and cancer cell interactions with bone. Cancer Metastasis Rev. 25, 589-600.
    Pubmed CrossRef
  98. Qin, X., Jiang, Q., Miyazaki, T., and Komori, T. (2019). Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells. Hum. Mol. Genet. 28, 896-911.
    Pubmed CrossRef
  99. Reinhold, M.I., and Naski, M.C. (2007). Direct interactions of Runx2 and canonical Wnt signaling induce FGF18. J. Biol. Chem. 282, 3653-3663.
    Pubmed CrossRef
  100. Riggio, A.I., and Blyth, K. (2017). The enigmatic role of RUNX1 in female-related cancers - current knowledge & future perspectives. FEBS J. 284, 2345-2362.
    Pubmed CrossRef
  101. Rooney, N., Riggio, A.I., Mendoza-Villanueva, D., Shore, P., Cameron, E.R., and Blyth, K. (2017). Runx genes in breast cancer and the mammary lineage. Adv. Exp. Med. Biol. 962, 353-368.
    Pubmed CrossRef
  102. Rubinfeld, B., Albert, I., Porfiri, E., Munemitsu, S., and Polakis, P. (1997). Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene. Cancer Res. 57, 4624-4630.
    Pubmed
  103. Rubinfeld, B., Souza, B., Albert, I., Muller, O., Chamberlain, S.H., Masiarz, F.R., Munemitsu, S., and Polakis, P. (1993). Association of the APC gene product with beta-catenin. Science 262, 1731-1734.
    Pubmed CrossRef
  104. Sadikovic, B., Thorner, P., Chilton-Macneill, S., Martin, J.W., Cervigne, N.K., Squire, J., and Zielenska, M. (2010). Expression analysis of genes associated with human osteosarcoma tumors shows correlation of RUNX2 overexpression with poor response to chemotherapy. BMC Cancer 10, 202.
    Pubmed KoreaMed CrossRef
  105. Sato, K., Tomizawa, Y., Iijima, H., Saito, R., Ishizuka, T., Nakajima, T., and Mori, M. (2006). Epigenetic inactivation of the RUNX3 gene in lung cancer. Oncol. Rep. 15, 129-135.
    Pubmed CrossRef
  106. Satoh, S., Daigo, Y., Furukawa, Y., Kato, T., Miwa, N., Nishiwaki, T., Kawasoe, T., Ishiguro, H., Fujita, M., Tokino, T., et al. (2000). AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 24, 245-250.
    Pubmed CrossRef
  107. Scheitz, C.J., and Tumbar, T. (2013). New insights into the role of Runx1 in epithelial stem cell biology and pathology. J. Cell. Biochem. 114, 985-993.
    Pubmed KoreaMed CrossRef
  108. Segditsas, S., and Tomlinson, I. (2006). Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25, 7531-7537.
    Pubmed CrossRef
  109. Shiraha, H., Nishina, S., and Yamamoto, K. (2011). Loss of runt-related transcription factor 3 causes development and progression of hepa­tocellular carcinoma. J. Cell. Biochem. 112, 745-749.
    Pubmed CrossRef
  110. Speidel, D., Wellbrock, J., and Abas, M. (2017). RUNX1 upregulation by cytotoxic drugs promotes apoptosis. Cancer Res. 77, 6818-6824.
    Pubmed CrossRef
  111. Steinhart, Z., and Angers, S. (2018). Wnt signaling in development and tissue homeostasis. Development 145, dev146589.
    Pubmed CrossRef
  112. Su, L.K., Vogelstein, B., and Kinzler, K.W. (1993). Association of the APC tumor suppressor protein with catenins. Science 262, 1734-1737.
    Pubmed CrossRef
  113. Sun, J., Li, B., Jia, Z., Zhang, A., Wang, G., Chen, Z., Shang, Z., Zhang, C., Cui, J., and Yang, W. (2018). RUNX3 inhibits glioma survival and invasion via suppression of the beta-catenin/TCF-4 signaling pathway. J. Neurooncol. 140, 15-26.
    Pubmed CrossRef
  114. Tanaka, S., Shiraha, H., Nakanishi, Y., Nishina, S., Matsubara, M., Horiguchi, S., Takaoka, N., Iwamuro, M., Kataoka, J., Kuwaki, K., et al. (2012). Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma. Int. J. Cancer 131, 2537-2546.
    Pubmed CrossRef
  115. Tang, N., Song, W.X., Luo, J., Luo, X., Chen, J., Sharff, K.A., Bi, Y., He, B.C., Huang, J.Y., Zhu, G.H., et al. (2009). BMP-9-induced osteogenic differentiation of mesenchymal progenitors requires functional canonical Wnt/beta-catenin signalling. J. Cell. Mol. Med. 13, 2448-2464.
    Pubmed KoreaMed CrossRef
  116. Taniuchi, I., Osato, M., and Ito, Y. (2012). Runx1: no longer just for leukemia. EMBO J. 31, 4098-4099.
    Pubmed KoreaMed CrossRef
  117. Tsukamoto, A.S., Grosschedl, R., Guzman, R.C., Parslow, T., and Varmus, H.E. (1988). Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619-625.
    Pubmed CrossRef
  118. Ugarte, G.D., Vargas, M.F., Medina, M.A., Leon, P., Necunir, D., Elorza, A.A., Gutierrez, S.E., Moon, R.T., Loyola, A., and De Ferrari, G.V. (2015). Wnt signaling induces transcription, spatial proximity, and translocation of fusion gene partners in human hematopoietic cells. Blood 126, 1785-1789.
    Pubmed CrossRef
  119. van der Horst, S.E.M., Cravo, J., Woollard, A., Teapal, J., and van den Heuvel, S. (2019). C. elegans Runx/CBFβ suppresses POP-1 TCF to con­vert asymmetric to proliferative division of stem cell-like seam cells. Development 146, dev.180034.
    Pubmed KoreaMed CrossRef
  120. Wang, B., Tian, T., Kalland, K.H., Ke, X., and Qu, Y. (2018). Targeting Wnt/beta-catenin signaling for cancer immunotherapy. Trends Pharmacol. Sci. 39, 648-658.
    Pubmed CrossRef
  121. Wang, J., Sinha, T., and Wynshaw-Boris, A. (2012). Wnt signaling in mam­malian development: lessons from mouse genetics. Cold Spring Harb. Perspect. Biol. 4, a007963.
    Pubmed KoreaMed CrossRef
  122. Whittle, M.C., and Hingorani, S.R. (2017). Runx3 and cell fate decisions in pancreas cancer. Adv. Exp. Med. Biol. 962, 333-352.
    Pubmed CrossRef
  123. Whittle, M.C., Izeradjene, K., Rani, P.G., Feng, L., Carlson, M.A., DelGiorno, K.E., Wood, L.D., Goggins, M., Hruban, R.H., Chang, A.E., et al. (2015). RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell 161, 1345-1360.
    Pubmed KoreaMed CrossRef
  124. Wu, J.Q., Seay, M., Schulz, V.P., Hariharan, M., Tuck, D., Lian, J., Du, J., Shi, M., Ye, Z., Gerstein, M., et al. (2012). Tcf7 is an important regulator of the switch of self-renewal and differentiation in a multipotential hematopoietic cell line. PLoS Genet. 8, e1002565.
    Pubmed KoreaMed CrossRef
  125. Xiao, W.H., and Liu, W.W. (2004). Hemizygous deletion and hyper­methylation of RUNX3 gene in hepatocellular carcinoma. World J. Gastro­enterol. 10, 376-380.
    Pubmed KoreaMed CrossRef
  126. Zhan, T., Rindtorff, N., and Boutros, M. (2017). Wnt signaling in cancer. Oncogene 36, 1461-1473.
    Pubmed KoreaMed CrossRef
  127. Zhang, Z., Cheng, L., Li, J., Farah, E., Atallah, N.M., Pascuzzi, P.E., Gupta, S., and Liu, X. (2018). Inhibition of the Wnt/beta-catenin pathway overcomes resistance to enzalutamide in castration-resistant prostate cancer. Cancer Res. 78, 3147-3162.
    Pubmed KoreaMed CrossRef


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