Browse > Article
http://dx.doi.org/10.14348/molcells.2019.0285

Oncogenic RUNX3: A Link between p53 Deficiency and MYC Dysregulation  

Date, Yuki (Department of Molecular Bone Biology, Graduate School of Biomedical Sciences, Nagasaki University)
Ito, Kosei (Department of Molecular Bone Biology, Graduate School of Biomedical Sciences, Nagasaki University)
Abstract
The RUNX transcription factors serve as master regulators of development and are frequently dysregulated in human cancers. Among the three family members, RUNX3 is the least studied, and has long been considered to be a tumor-suppressor gene in human cancers. This idea is mainly based on the observation that RUNX3 is inactivated by genetic/epigenetic alterations or protein mislocalization during the initiation of tumorigenesis. Recently, this paradigm has been challenged, as several lines of evidence have shown that RUNX3 is upregulated over the course of tumor development. Resolving this paradox and understanding how a single gene can exhibit both oncogenic and tumor-suppressive properties is essential for successful drug targeting of RUNX. We propose a simple explanation for the duality of RUNX3: p53 status. In this model, p53 deficiency causes RUNX3 to become an oncogene, resulting in aberrant upregulation of MYC.
Keywords
c-Myc; p53; RUNX3;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Rodriguez-Ubreva, J., Ciudad, L., van Oevelen, C., Parra, M., Graf, T., and Ballestar, E. (2014). C/EBPa-mediated activation of microRNAs 34a and 223 inhibits Lef1 expression to achieve efficient reprogramming into macrophages. Mol. Cell. Biol. 34, 1145-1157.   DOI
2 Sachdeva, M., Zhu, S., Wu, F., Wu, H., Walia, V., Kumar, S., Elble, R., Watabe, K., and Mo, Y.Y. (2009). p53 Represses c-Myc through induction of the tumor suppressor miR-145. Proc. Natl. Acad. Sci. U. S. A. 106, 3207-3212.   DOI
3 Schmitt, C.A., McCurrach, M.E., de Stanchina, E., Wallace-Brodeur, R.R., and Lowe, S.W. (1999). INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev. 13, 2670-2677.   DOI
4 Selvarajan, V., Osato, M., Nah, G.S.S., Yan, J., Chung, T.H., Voon, D.C.C., Ito, Y., Ham, M.F., Salto-Tellez, M., Shimizu, N., et al. (2017). RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC. Leukemia 31, 2219-2227.   DOI
5 Sherr, C.J. (2006). Divorcing ARF and p53: an unsettled case. Nat. Rev. Cancer 6, 663-673.   DOI
6 Shi, J., Whyte, W.A., Zepeda-Mendoza, C.J., Milazzo, J.P., Shen, C., Roe, J.S., Minder, J.L., Mercan, F., Wang, E., Eckersley-Maslin, M.A., et al. (2013). Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 27, 2648-2662.   DOI
7 Shimizu, K., Yamagata, K., Kurokawa, M., Mizutani, S., Tsunematsu, Y., and Kitabayashi, I. (2013). Roles of AML1/RUNX1 in T-cell malignancy induced by loss of p53. Cancer Sci. 104, 1033-1038.   DOI
8 Chi, X.Z., Yang, J.O., Lee, K.Y., Ito, K., Sakakura, C., Li, Q.L., Kim, H.R., Cha, E.J., Lee, Y.H., Kaneda, A., et al. (2005). RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor $\beta$-activated SMAD. Mol. Cell. Biol. 25, 8097-8107.   DOI
9 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.   DOI
10 Cunningham, L., Finckbeiner, S., Hyde, R.K., Southall, N., Marugan, J., Yedavalli, V.R.K., Dehdashti, S.J., Reinhold, W.C., Alemu, L., Zhao, L., et al. (2012). Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBF$\beta$ interaction. Proc. Natl. Acad. Sci. U. S. A. 109, 14592-14597.   DOI
11 Damdinsuren, A., Matsushita, H., Ito, M., Tanaka, M., Jin, G., Tsukamoto, H., Asai, S., Ando, K., and Miyachi, H. (2015). FLT3-ITD drives Ara-C resistance in leukemic cells via the induction of RUNX3. Leuk. Res. 39, 1405-1413.   DOI
12 David, C.J. and Massague, J. (2018). Contextual determinants of TGF$\beta$ action in development, immunity and cancer. Nat. Rev. Mol. Cell Biol. 19, 419-435.   DOI
13 Donehower, L.A. and Lozano, G. (2009). 20 years studying p53 functions in genetically engineered mice. Nat. Rev. Cancer 9, 831-841.   DOI
14 Eferl, R. and Wagner, E.F. (2003). AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859-868.   DOI
15 Herranz, D., Ambesi-Impiombato, A., Palomero, T., Schnell, S.A., Belver, L., Wendorff, A.A., Xu, L., Castillo-Martin, M., Llobet-Navas, D., Cordon-Cardo, C., et al. (2014). A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20, 1130-1137.   DOI
16 Tirode, F., Surdez, D., Ma, X., Parker, M., Le Deley, M.C., Bahrami, A., Zhang, Z., Lapouble, E., Grossetête-Lalami, S., Rusch, M., et al. (2014). Genomic landscape of Ewing sarcoma defines an aggressive subtype with coassociation of STAG2 and TP53 mutations. Cancer Discov. 4, 1342-1353.   DOI
17 Eischen, C.M., Weber, J.D., Roussel, M.F., Sherr, C.J., and Cleveland, J.L. (1999). Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13, 2658-2669.   DOI
18 Hay, J., Gilroy, K., Huser, C., Kilbey, A., McDonald, A., MacCallum, A., Holroyd, A., Cameron, E., and Neil, J.C. (2019). Collaboration of MYC and RUNX2 in lymphoma simulates T-cell receptor signaling and attenuates p53 pathway activity. J. Cell. Biochem. 120, 18332-18345.   DOI
19 He, L., He, X., Lim, L.P., de Stanchina, E., Xuan, Z., Liang, Y., Xue, W., Zender, L., Magnus, J., Ridzon, D., et al. (2007). A microRNA component of the p53 tumour suppressor network. Nature 447, 1130-1134.   DOI
20 He, Y., de Castro, L.F., Shin, M.H., Dubois, W., Yang, H.H., Jiang, S., Mishra, P.J., Ren, L., Gou, H., Lal, A., et al. (2015). p53 Loss increases the osteogenic differentiation of bone marrow stromal cells. Stem Cells 33, 1304-1319.   DOI
21 Ho, J.S.L., Ma, W., Mao, D.Y.L., and Benchimol, S. (2005). p53-Dependent transcriptional repression of c-myc is required for G1 cell cycle arrest. Mol. Cell. Biol. 25, 7423-7431.   DOI
22 Ikushima, H. and Miyazono, K. (2010). TGFbeta signalling: a complex web in cancer progression. Nat. Rev. Cancer 10, 415-424.   DOI
23 Ito, K., Chuang, L.S.H., 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.   DOI
24 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.   DOI
25 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.   DOI
26 van der Deen, M., Taipaleenmäki, H., Zhang, Y., Teplyuk, N.M., Gupta, A., Cinghu, S., Shogren, K., Maran, A., Yaszemski, M.J., Ling, L., et al. (2013). MicroRNA-34c inversely couples the biological functions of the runtrelated transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma. J. Biol. Chem. 288, 21307-21319.   DOI
27 Whittle, M.C. and Hingorani, S.R. (2017). Runx3 and cell fate decisions in pancreas cancer. Adv. Exp. Med. Biol. 962, 333-352.   DOI
28 Wotton, S.F., Blyth, K., Kilbey, A., Jenkins, A., Terry, A., Bernardin-Fried, F., Friedman, A.D., Baxter, E.W., Neil, J.C., and Cameron, E.R. (2004). RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53. Oncogene 23, 5476-5486.   DOI
29 Shin, M.H., He, Y., Marrogi, E., Piperdi, S., Ren, L., Khanna, C., Gorlick, R., Liu, C., and Huang, J. (2016). A RUNX2-mediated epigenetic regulation of the survival of p53 defective cancer cells. PLoS Genet. 12, e1005884.   DOI
30 Ito, K., Lim, A.C.B., Salto-Tellez, M., Motoda, L., Osato, M., Chuang, L.S.H., Lee, C.W.L., Voon, D.C.C., Koo, J.K.W., Wang, H., et al. (2008). RUNX3 attenuates $\beta$-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell 14, 226-237.   DOI
31 Ito, Y., Bae, S.C., and Chuang, L.S.H. (2015). The RUNX family: developmental regulators in cancer. Nat. Rev. Cancer 15, 81-95.   DOI
32 Kubota, S., Tokunaga, K., Umezu, T., Yokomizo-Nakano, T., Sun, Y., Oshima, M., Tan, K.T., Yang, H., Kanai, A., Iwanaga, E., et al. (2019). Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm. Nat. Commun. 10, 1653.   DOI
33 Lee, C.W., Chuang, L.S., Kimura, S., Lai, S.K., Ong, C.W., Yan, B., Salto-Tellez, M., Choolani, M., and Ito, Y. (2011b). RUNX3 functions as an oncogene in ovarian cancer. Gynecol. Oncol. 122, 410-417.   DOI
34 Lee, J.H., Pyon, J.K., Kim, D.W., Lee, S.H., Nam, H.S., Kang, S.G., Kim, C.H., Lee, Y.J., Chun, J.S., and Cho, M.K. (2011a). Expression of RUNX3 in skin cancers. Clin. Exp. Dermatol. 36, 769-774.   DOI
35 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. (2019). RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restrictionpoint. Nat. Commun. 10, 1897.   DOI
36 Lee, J.W., Van wijnen, A., and Bae, S.C. (2017). RUNX3 and p53: how two tumor suppressors cooperate against oncogenic Ras? Adv. Exp. Med. Biol. 962, 321-332.   DOI
37 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.   DOI
38 Yano, T., Ito, K., Fukamachi, H., Chi, X.Z., Wee, H.J., Inoue, K.I., Ida, H., Bouillet, P., Strasser, A., Bae, S.C., et al. (2006). The RUNX3 tumor suppressor upregulates Bim in gastric epithelial cells undergoing transforming growth factor beta-induced apoptosis. Mol. Cell. Biol. 26, 4474-4488.   DOI
39 Yamada, C., Ozaki, T., Ando, K., Suenaga, Y., Inoue, K.I., Ito, Y., Okoshi, R., Kageyama, H., Kimura, H., Miyazaki, M., et al. (2010). RUNX3 modulates DNA damage-mediated phosphorylation of tumor suppressor p53 at Ser-15 and acts as a co-activator for p53. J. Biol. Chem. 285, 16693-16703.   DOI
40 Lengner, C.J., Steinman, H.A., Gagnon, J., Smith, T.W., Henderson, J.E., Kream, B.E., Stein, G.S., Lian, J.B., and Jones, S.N. (2006). Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. J. Cell Biol. 172, 909-921.   DOI
41 Yoshida, C.A., Yamamoto, H., Fujita, T., Furuichi, T., Ito, K., Inoue, K.I., Yamana, K., Zanma, A., Takada, K., Ito, Y., et al. (2004). Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog. Genes Dev. 18, 952-963.   DOI
42 Young, K.H., Leroy, K., Moller, M.B., Colleoni, G.W.B., Sanchez-Beato, M., Kerbauy, F.R., Haioun, C., Eickhoff, J.C., Young, A.H., Gaulard, P., et al. (2008). Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 112, 3088-3098.
43 Zhang, D.X. and Glass, C.K. (2013). Towards an understanding of cellspecific functions of signal-dependent transcription factors. J. Mol. Endocrinol. 51, T37-T50.   DOI
44 Zindy, F., Eischen, C.M., Randle, D.H., Kamijo, T., Cleveland, J.L., Sherr, C.J., and Roussel, M.F. (1998). Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12, 2424-2433.   DOI
45 Ma, X., Liu, Y., Liu, Y., Alexandrov, L.B., Edmonson, M.N., Gawad, C., Zhou, X., Li, Y., Rusch, M.C., Easton, J., et al. (2018). Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature 555, 371-376.   DOI
46 Li, Q.L., Ito, K., Sakakura, C., Fukamachi, H., Inoue, K.I., 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.   DOI
47 Link, V.M., Duttke, S.H., Chun, H.B., Holtman, I.R., Westin, E., Hoeksema, M.A., Abe, Y., Skola, D., Romanoski, C.E., Tao, J., et al. (2018). Analysis of genetically diverse macrophages reveals local and domain-wide mechanisms that control transcription factor binding and function. Cell 173, 1796-1809.   DOI
48 Lobry, C., Oh, P., Mansour, M.R., Look, A.T., and Aifantis, I. (2014). Notch signaling: switching an oncogene to a tumor suppressor. Blood 123, 2451-2459.   DOI
49 Martins, C.P., Brown Swigart, L., and Evan, G.I. (2006). Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323-1334.   DOI
50 Morita, K., Suzuki, K., Maeda, S., Matsuo, A., Mitsuda, Y., Tokushige, C., Kashiwazaki, G., Taniguchi, J., Maeda, R., Noura, M., et al. (2017). Genetic regulation of the RUNX transcription factor family has antitumor effects. J. Clin. Invest. 127, 2815-2828.   DOI
51 O'Shea, D., O'Riain, C., Taylor, C., Waters, R., Carlotti, E., MacDougall, F., Gribben, J., Rosenwald, A., Ott, G., Rimsza, L.M., et al. (2008). The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood 112, 3126-3129.
52 Moroishi, T., Hansen, C.G., and Guan, K.L. (2015). The emerging roles of YAP and TAZ in cancer. Nat. Rev. Cancer 15, 73-79.   DOI
53 Murphy, D.J., Junttila, M.R., Pouyet, L., Karnezis, A., Shchors, K., Bui, D.A., Brown Swigart, L., Johnson, L., and Evan, G.I. (2008). Distinct thresholds govern Myc's biological output in vivo. Cancer Cell 14, 447-457.   DOI
54 Neil, J.C., Gilroy, K., Borland, G., Hay, J., Terry, A., and Kilbey, A. (2017). The RUNX genes as conditional oncogenes: insights from retroviral targeting and mouse models. Adv. Exp. Med. Biol. 962, 247-264.   DOI
55 Nevadunsky, N.S., Barbieri, J.S., Kwong, J., Merritt, M.A., Welch, W.R., Berkowitz, R.S., and Mok, S.C. (2009). RUNX3 protein is overexpressed in human epithelial ovarian cancer. Gynecol. Oncol. 112, 325-330.   DOI
56 Okada, N., Lin, C.P., Ribeiro, M.C., Biton, A., Lai, G., He, X., Bu, P., Vogel, H., Jablons, D.M., Keller, A.C., et al. (2014). A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression. Genes Dev. 28, 438-450.   DOI
57 Ozaki, T., Nakagawara, A., and Nagase, H. (2013). RUNX family participates in the regulation of p53-dependent DNA damage response. Int. J. Genomics 2013, 271347.   DOI
58 Perkins, N.D. (2004). NF-kappaB: tumor promoter or suppressor? Trends Cell Biol. 14, 64-69.   DOI
59 Porter, J.R., Fisher, B.E., Baranello, L., Liu, J.C., Kambach, D.M., Nie, Z., Koh, W.S., Luo, J., Stommel, J.M., Levens, D., et al. (2017). Global inhibition with specific activation: how p53 and MYC redistribute the transcriptome in the DNA double-strand break response. Mol. Cell 67, 1013-1025.   DOI
60 Phesse, T.J., Myant, K.B., Cole, A.M., Ridgway, R.A., Pearson, H., Muncan, V., van den Brink, G.R., Vousden, K.H., Sears, R., Vassilev, L.T., et al. (2014). Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo. Cell Death Differ. 21, 956-966.   DOI
61 Bauer, O., Sharir, A., Kimura, A., Hantisteanu, S., Takeda, S., and Groner, Y. (2015). Loss of osteoblast Runx3 produces severe congenital osteopenia. Mol. Cell. Biol. 35, 1097-1109.   DOI
62 Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B., Solari, A., Bobisse, S., Rondina, M.B., Guzzardo, V., et al. (2009). A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 137, 87-98.   DOI
63 Bae, S.C., Kolinjivadi, A.M., and Ito, Y. (2019). Functional relationship between p53 and RUNX proteins. J. Mol. Cell Biol. 11, 224-230.   DOI
64 Barghout, S.H., Zepeda, N., Vincent, K., Azad, A.K., Xu, Z., Yang, C., Steed, H., Postovit, L.M., and Fu, Y. (2015). RUNX3 contributes to carboplatin resistance in epithelial ovarian cancer cells. Gynecol. Oncol. 138, 647-655.   DOI
65 Belver, L. and Ferrando, A. (2016). The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat. Rev. Cancer 16, 494-507.   DOI
66 Bledsoe, K.L., McGee-Lawrence, M.E., Camilleri, E.T., Wang, X., Riester, S.M., van Wijnen, A.J., Oliveira, A.M., and Westendorf, J.J. (2014). RUNX3 facilitates growth of Ewing sarcoma cells. J. Cell. Physiol. 229, 2049-2056.   DOI
67 Bushweller, J.H. (2019). Targeting transcription factors in cancer - from undruggable to reality. Nat. Rev. Cancer 19, 611-624.   DOI
68 Pulikkan, J.A., Hegde, M., Ahmad, H.M., Belaghzal, H., Illendula, A., Yu, J., O’Hagan, K., Ou, J., Müller-Tidow, C., Wolfe, S.A., et al. (2018). CBF$\beta$-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia. Cell 174, 172-186.   DOI
69 Blyth, K., Terry, A., Mackay, N., Vaillant, F., Bell, M., Cameron, E.R., Neil, J.C., and Stewart, M. (2001). Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging. Oncogene 20, 295-302.   DOI
70 Blyth, K., Terry, A., O'Hara, M., Baxter, E.W., Campbell, M., Stewart, M., Donehower, L.A., Onions, D.E., Neil, J.C., and Cameron, E.R. (1995). Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss. Oncogene 10, 1717-1723.
71 Chang, T.L., Ito, K., Ko, T.K., Liu, Q., Salto-Tellez, M., Yeoh, K.G., Fukamachi, H., and Ito, Y. (2010). Claudin-1 has tumor suppressive activity and is a direct target of RUNX3 in gastric epithelial cells. Gastroenterology 138, 255-265.   DOI
72 Chen, X., Bahrami, A., Pappo, A., Easton, J., Dalton, J., Hedlund, E., Ellison, D., Shurtleff, S., Wu, G., Wei, L., et al. (2014). Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104-112.   DOI
73 Chen, H., Crosley, P., Azad, A.K., Gupta, N., Gokul, N., Xu, Z., Weinfeld, M., Postovit, L.M., Pangas, S.A., Hitt, M.M., et al. (2019). RUNX3 promotes the tumorigenic phenotype in KGN, a human granulosa cell tumor-derived cell line. Int. J. Mol. Sci. 20, E3471.   DOI
74 Chuang, L.S., Ito, K., and Ito, Y. (2017). Roles of RUNX in solid tumors. Adv. Exp. Med. Biol. 962, 299-320.   DOI
75 Chuang, L.S.H., Ito, K., and Ito, Y. (2013). RUNX family: regulation and diversification of roles through interacting proteins. Int. J. Cancer 132, 1260-1271.   DOI