Mol. Cells 2020; 43(2): 97~98  https://doi.org/10.14348/molcells.2020.2320
Tour d’Horizon of Recent Advances in RUNX Family Gene Research
Suk-Chul Bae *
Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju 28644, Korea
*Correspondence: scbae@chungbuk.ac.kr
Received December 20, 2019; Accepted December 20, 2019.; Published online February 6, 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/).
Body

RUNX family transcription factors are essential regulators of diverse developmental processes, including cell proliferation, differentiation, apoptosis, and cell lineage specification (Ito et al., 2015). RUNX genes were independently identified as the fly segmentation gene Runt, a leukemia associated gene, and the subunit of a virus enhancer binding protein. Mammals possess three RUNX genes, RUNX1, RUNX2, and RUNX3, which form a heterodimeric complex in the presence of a b subunit, CBFb. Although these RUNX family members bind to the same nucleotide sequence (PuACCPuCA/TGPyGGTPy), each member has distinct tissue-specific roles (Ito et al., 2015). All are deregulated in one way or another in human diseases, indicating they are intimately involved in the pathogenesis of human disease. This special issue describes the roles of RUNX proteins in developmental processes and tumorigenesis.

The regulatory function of RUNX1 in hematopoiesis was first revealed when Runx1 was disrupted in mice (Okuda et al., 1996). RUNX1 gene disruptions caused by chromosomal translocations and mutations are frequently detected in hematological diseases, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS) (Bellissimo and Speck, 2017), indicating that RUNX1 is intimately involved in hematopoiesis and hematopoietic lineage specification and its functional dysregulation is associated with leukemia. More recent studies show that RUNX1 is also associated with various solid tumors.

The regulatory function of RUNX2 in osteogenesis was first revealed when Runx2 was disrupted in mice (Komori et al., 1997; Otto et al., 1997). Based on these studies, further work showed that human autosomal dominant bone disease cleidocranial dysplasia (CCD) is caused by RUNX2 haploinsufficiency (Lee et al., 1997; Mundlos et al., 1997; Otto et al., 1997), establishing Runx2 as a master regulator of osteogenesis. Overexpression of RUNX2 occurs in various solid tumors including osteosarcoma, lymphoma, and breast cancer, indicating that functional dysregulation of RUNX2 is associated with tumorigenesis (Blyth et al., 2006; Ferrari et al., 2013; Sadikovic et al., 2010).

Runx3 knockout mice, the result of a collaboration between my laboratory and that of Yoshiaki Ito (Li et al., 2002), cancer cell lines, and surgically dissected cancer tissues revealed that loss of RUNX3 expression occurs in, and is causally related to, gastric cancer (Li et al., 2002). RUNX3 inactivation in gastric cancer is the combined result of its hemizygous deletion and silencing by DNA hypermethylation (Li et al., 2002). Silencing of RUNX3 by DNA hypermethylation was also observed in various other cancers, suggesting that RUNX3 functions as a tumor suppressor (Ito et al., 2015). Subsequent studies revealed that RUNX3 plays key roles in suppressing not only gastric cancer but also lung cancer (Lee et al., 2013). RUNX3 also functions as an oncogene is some cancers. For example, RUNX3 is overexpressed in head and neck cancer, squamous cell carcinoma (SCC), epithelial ovarian cancer, and basal cell carcinoma (Lee et al., 2011; Salto-Tellez et al., 2006; Tsunematsu et al., 2009). In pancreatic cancer, RUNX3 functions as a tumor suppressor at the early stage and as an oncogene at the late stage of tumor progression (Whittle et al., 2015). These opposing roles of RUNX3 can be reconciled by the recent observation that RUNX3 is important for context-dependent cell fate decisions at the G1 restriction point, i.e., it determines whether cells progress through the cell cycle or enter apoptosis (Lee et al., 2019a). Therefore, RUNX3 overexpression has the potential to disturb restriction point regulation and cause unprogrammed cell proliferation in some tissues.

RUNX family members have both tumor suppressive and oncogenic activity. What makes RUNX a tumor suppressor or an oncogene? This question can only be answered after we know more about how cancers develop and how RUNX genes determine cell fate, which is critical for regulating developmental processes in diverse tissues. In this regard, it is worth mentioning that restriction point regulation, which is critical in deciding whether cells proliferate, differentiate and undergo apoptosis, is disrupted in nearly all cancer cells. Recently, all three RUNX family members were shown to be involved in restriction point regulation (Lee et al., 2019a; 2019b). It is worth emphasizing that RUNX family members bind to the same nucleotide sequence. Therefore, the results of all these studies suggest that the diverse roles of RUNX family members can be explained, at least partly, by their participation in a common cell fate decision mechanism that makes cell type-specific and context-dependent decisions.

REFERENCES
  1. Bellissimo, D.C., and Speck, N.A. (2017). RUNX1 mutations in inherited and sporadic leukemia. Front. Cell Dev. Biol. 5, 111.
    Pubmed KoreaMed CrossRef
  2. Blyth, K., Vaillant, F., Hanlon, L., Mackay, N., Bell, M., Jenkins, A., Neil, J.C., and Cameron, E.R. (2006). RUNX2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo. Cancer Res. 66, 2195-2201.
    Pubmed CrossRef
  3. Ferrari, N., McDonald, L., Morris, J.S., Cameron, E.R., and Blyth, K. (2013). RUNX2 in mammary gland development and breast cancer. J. Cell. Physiol. 228, 1137-1142.
    Pubmed CrossRef
  4. 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
  5. 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
  6. Lee, B., Thirunavukkarasu, K., Zhou, L., Pastore, L., Baldini, A., Hecht, J., Geoffroy, V., Ducy, P., and Karsenty, G. (1997). Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat. Genet. 16, 307-310.
    Pubmed CrossRef
  7. Lee, C.W., Chuang, L.S., Kimura, S., Lai, S.K., Ong, C.W., Yan, B., Salto-Tellez, M., Choolani, M., and Ito, Y. (2011). RUNX3 functions as an oncogene in ovarian cancer. Gynecol. Oncol. 122, 410-417.
    Pubmed CrossRef
  8. Lee, J.W., Kim, D.M., Jang, J.W., Park, T.G., Song, S.H., Lee, Y.S., Chi, X.Z., Park, I.Y., Hyun, J.W., Ito, Y., et al. (2019a). RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restriction-point. Nat. Commun. 10, 1897.
    Pubmed KoreaMed CrossRef
  9. Lee, J.W., Park, T.G., and Bae, S.C. (2019b). Involvement of RUNX and BRD family members in restriction point. Mol. Cells 42, 836-839.
    Pubmed KoreaMed CrossRef
  10. 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
  11. 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
  12. Mundlos, S., Otto, F., Mundlos, C., Mulliken, J.B., Aylsworth, A.S., Albright, S., Lindhout, D., Cole, W.G., Henn, W., Knoll, J.H., et al. (1997). Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773-779.
    Pubmed CrossRef
  13. 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
  14. 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
  15. 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
  16. Salto-Tellez, M., Peh, B.K., Ito, K., Tan, S.H., Chong, P.Y., Han, H.C., Tada, K., Ong, W.Y., Soong, R., Voon, D.C., et al. (2006). RUNX3 protein is overexpressed in human basal cell carcinomas. Oncogene 25, 7646-7649.
    Pubmed CrossRef
  17. Tsunematsu, T., Kudo, Y., Iizuka, S., Ogawa, I., Fujita, T., Kurihara, H., Abiko, Y., and Takata, T. (2009). RUNX3 has an oncogenic role in head and neck cancer. PLoS One 4, e5892
    Pubmed KoreaMed CrossRef
  18. 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


Current Issue

30 September 2020 Volume 43,
Number 9, pp. 763~840

This Article


Cited By Articles
  • CrossRef (0)

Social Network Service
Services

Indexed in

  • Science Central
  • CrossMark