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Gene Review

RUNX3  -  runt-related transcription factor 3

Homo sapiens

Synonyms: AML2, Acute myeloid leukemia 2 protein, CBF-alpha-3, CBFA3, Core-binding factor subunit alpha-3, ...
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Disease relevance of RUNX3


High impact information on RUNX3

  • Causal relationship between the loss of RUNX3 expression and gastric cancer [7].
  • Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region [7].
  • Our data indicate that cytokine gene expression in T(H)1 cells may be controlled by a feed-forward regulatory circuit in which T-bet induces Runx3 and then 'partners' with Runx3 to direct lineage-specific gene activation and silencing [8].
  • In this issue of Neuron, three papers demonstrate that the Runx transcription factors, Runx1 and Runx3, respectively regulate the molecular identities and spinal terminations of TrkA+ nociceptive neurons and TrkC+ proprioceptive neurons [9].
  • Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord [10].

Chemical compound and disease context of RUNX3


Biological context of RUNX3

  • Mislocalization of the protein, with or without methylation, seems to account for RUNX3 inactivation in the vast majority of the tumors [2].
  • Fifty percent of the breast cancer cell lines (n = 19) showed hypermethylation at the promoter region and displayed significantly lower levels of RUNX3 mRNA expression (P < 0.0001) and protein (P < 0.001) [2].
  • Stable expression of RUNX3 in MDA-MB-231 breast cancer cells led to a more cuboidal phenotype, significantly reduced invasiveness in Matrigel invasion assays, and suppressed tumor formation in immunodeficient mice [2].
  • Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation [16].
  • Furthermore, RUNX1 and RUNX3 associate with SUV39H1, a histone methyltransferase involved in gene silencing [17].

Anatomical context of RUNX3


Associations of RUNX3 with chemical compounds


Physical interactions of RUNX3

  • According to recent data reported by Yamamura et al., (J Biol Chem 2006; 281:5267-76), RUNX3 interacts with FoxO3a/FKHRL1 expressed in gastric cancer cells to activate Bim and induce apoptosis [24].
  • Among them, PEBP2alphaC/CBFA3/AML2 forms a complex with Smad3 and stimulates transcription of the germline Ig Calpha promoter in a cooperative manner, for which binding of both factors to their specific binding sites is essential [25].

Regulatory relationships of RUNX3

  • RESULTS: RUNX3 gene transfer suppressed VEGF expression in human gastric cancer cells [4].
  • Knockdown of RUNX3 in these cells induces RUNX1 expression and inhibits cell proliferation, directly showing that RUNX proteins can regulate B-cell growth [26].
  • The functional relevance of these elements are illustrated by the fact that RUNX3 overexpression leads to enhanced CD11a/CD18 levels, whereas RUNX1-ETO-expressing cells exhibit a weak/absent CD11a/CD18 integrin cell surface expression [20].
  • RUNX3 negatively regulates CD36 expression in myeloid cell lines [27].
  • Luciferase reporter assay suggested that Runx3 inhibited the promoter activity of the MDR-1 and MRP-1 promoter in SGC7901 cells [12].

Other interactions of RUNX3

  • A tumor suppressor function has been attributed to RUNX3, a member of the RUNX family of transcription factors [2].
  • Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk [28].
  • In gastric cancer specimens, loss or decrease in RUNX3 expression inversely associated with increased VEGF expression and elevated microvessel formation [4].
  • RUNX1 is involved in hematopoiesis, RUNX2 has multiple roles in osteogenesis and RUNX3 is associated with neural and gut development [29].
  • In conclusion, TGFBR2 mutation is associated with CIMP-high and indirectly with RUNX3 methylation [5].
  • The results showed that RUNX3 is a target for repression by EZH2 and indicated an underlying mechanism of the functional role of EZH2 overexpression on cancer cell proliferation [30].

Analytical, diagnostic and therapeutic context of RUNX3


  1. RUNX3 suppresses gastric epithelial cell growth by inducing p21(WAF1/Cip1) expression in cooperation with transforming growth factor {beta}-activated SMAD. 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., Ushijima, T., Kim, W.J., Ito, Y., Bae, S.C. Mol. Cell. Biol. (2005) [Pubmed]
  2. RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Lau, Q.C., Raja, E., Salto-Tellez, M., Liu, Q., Ito, K., Inoue, M., Putti, T.C., Loh, M., Ko, T.K., Huang, C., Bhalla, K.N., Zhu, T., Ito, Y., Sukumar, S. Cancer Res. (2006) [Pubmed]
  3. Transcriptional cross-regulation of RUNX1 by RUNX3 in human B cells. Spender, L.C., Whiteman, H.J., Karstegl, C.E., Farrell, P.J. Oncogene (2005) [Pubmed]
  4. RUNX3 Inhibits the Expression of Vascular Endothelial Growth Factor and Reduces the Angiogenesis, Growth, and Metastasis of Human Gastric Cancer. Peng, Z., Wei, D., Wang, L., Tang, H., Zhang, J., Le, X., Jia, Z., Li, Q., Xie, K. Clin. Cancer Res. (2006) [Pubmed]
  5. TGFBR2 mutation is correlated with CpG island methylator phenotype in microsatellite instability-high colorectal cancer. Ogino, S., Kawasaki, T., Ogawa, A., Kirkner, G.J., Loda, M., Fuchs, C.S. Hum. Pathol. (2007) [Pubmed]
  6. Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis. Sakakura, C., Miyagawa, K., Fukuda, K.I., Nakashima, S., Yoshikawa, T., Kin, S., Nakase, Y., Ida, H., Yazumi, S., Yamagishi, H., Okanoue, T., Chiba, T., Ito, K., Hagiwara, A., Ito, Y. Oncogene (2007) [Pubmed]
  7. Causal relationship between the loss of RUNX3 expression and gastric cancer. 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., Kim, H.M., Kim, W.J., Yamamoto, H., Yamashita, N., Yano, T., Ikeda, T., Itohara, S., Inazawa, J., Abe, T., Hagiwara, A., Yamagishi, H., Ooe, A., Kaneda, A., Sugimura, T., Ushijima, T., Bae, S.C., Ito, Y. Cell (2002) [Pubmed]
  8. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Djuretic, I.M., Levanon, D., Negreanu, V., Groner, Y., Rao, A., Ansel, K.M. Nat. Immunol. (2007) [Pubmed]
  9. "Runx"ing towards sensory differentiation. Zhong, J., Pevny, L., Snider, W.D. Neuron (2006) [Pubmed]
  10. Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord. Chen, A.I., de Nooij, J.C., Jessell, T.M. Neuron (2006) [Pubmed]
  11. Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. Goel, A., Arnold, C.N., Tassone, P., Chang, D.K., Niedzwiecki, D., Dowell, J.M., Wasserman, L., Compton, C., Mayer, R.J., Bertagnolli, M.M., Boland, C.R. Int. J. Cancer (2004) [Pubmed]
  12. Tumor suppressor gene Runx3 sensitizes gastric cancer cells to chemotherapeutic drugs by downregulating Bcl-2, MDR-1 and MRP-1. Guo, C., Ding, J., Yao, L., Sun, L., Lin, T., Song, Y., Sun, L., Fan, D. Int. J. Cancer (2005) [Pubmed]
  13. Therapy-related acute myeloid leukemia with t(8;21) in a child with previous Ewing's sarcoma. Lesesve, J.F., Schneider, P., Dolgopolov, I., Bastard, C., Lenormand, B., Cambon-Michot, E., Callat, M.P., Cavelier, B., Tron, P.H., Vannier, J.P. Med. Pediatr. Oncol. (1997) [Pubmed]
  14. Isolation and characterization of daunorubicin-resistant AML-2 sublines. Choi, C.H., Ling, V. Mol. Cells (1997) [Pubmed]
  15. Adaphostin has significant and selective activity against chronic and acute myeloid leukemia cells. Orsolic, N., Golemovic, M., Quintás-Cardama, A., Scappini, B., Manshouri, T., Chandra, J., Basic, I., Giles, F., Kantarjian, H., Verstovsek, S. Cancer Sci. (2006) [Pubmed]
  16. Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. Jin, Y.H., Jeon, E.J., Li, Q.L., Lee, Y.H., Choi, J.K., Kim, W.J., Lee, K.Y., Bae, S.C. J. Biol. Chem. (2004) [Pubmed]
  17. Role of RUNX family members in transcriptional repression and gene silencing. Durst, K.L., Hiebert, S.W. Oncogene (2004) [Pubmed]
  18. Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer. Sakakura, C., Hagiwara, A., Miyagawa, K., Nakashima, S., Yoshikawa, T., Kin, S., Nakase, Y., Ito, K., Yamagishi, H., Yazumi, S., Chiba, T., Ito, Y. Int. J. Cancer (2005) [Pubmed]
  19. Expression of RUNX3 protein in human gastric mucosa, intestinal metaplasia and carcinoma. Osaki, M., Moriyama, M., Adachi, K., Nakada, C., Takeda, A., Inoue, Y., Adachi, H., Sato, K., Oshimura, M., Ito, H. Eur. J. Clin. Invest. (2004) [Pubmed]
  20. RUNX3 regulates the activity of the CD11a and CD49d integrin gene promoters. Domínguez-Soto, A., Relloso, M., Vega, M.A., Corbí, A.L., Puig-Kröger, A. Immunobiology (2005) [Pubmed]
  21. Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Ku, J.L., Kang, S.B., Shin, Y.K., Kang, H.C., Hong, S.H., Kim, I.J., Shin, J.H., Han, I.O., Park, J.G. Oncogene (2004) [Pubmed]
  22. Epigenetic inactivation of the RUNX3 gene in lung cancer. Sato, K., Tomizawa, Y., Iijima, H., Saito, R., Ishizuka, T., Nakajima, T., Mori, M. Oncol. Rep. (2006) [Pubmed]
  23. Quantitative assessment of RUNX3 methylation in neoplastic and non-neoplastic gastric epithelia using a DNA microarray. So, K., Tamura, G., Honda, T., Homma, N., Endoh, M., Togawa, N., Nishizuka, S., Motoyama, T. Pathol. Int. (2006) [Pubmed]
  24. How does the human RUNX3 gene induce apoptosis in gastric cancer? Latest data, reflections and reactions. Vogiatzi, P., De Falco, G., Claudio, P.P., Giordano, A. Cancer Biol. Ther. (2006) [Pubmed]
  25. Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter. Hanai, J., Chen, L.F., Kanno, T., Ohtani-Fujita, N., Kim, W.Y., Guo, W.H., Imamura, T., Ishidou, Y., Fukuchi, M., Shi, M.J., Stavnezer, J., Kawabata, M., Miyazono, K., Ito, Y. J. Biol. Chem. (1999) [Pubmed]
  26. RUNX expression and function in human B cells. Whiteman, H.J., Farrell, P.J. Crit. Rev. Eukaryot. Gene Expr. (2006) [Pubmed]
  27. RUNX3 negatively regulates CD36 expression in myeloid cell lines. Puig-Kröger, A., Domínguez-Soto, A., Martínez-Muñoz, L., Serrano-Gómez, D., Lopez-Bravo, M., Sierra-Filardi, E., Fernández-Ruiz, E., Ruiz-Velasco, N., Ardavín, C., Groner, Y., Tandon, N., Corbí, A.L., Vega, M.A. J. Immunol. (2006) [Pubmed]
  28. Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Schulmann, K., Sterian, A., Berki, A., Yin, J., Sato, F., Xu, Y., Olaru, A., Wang, S., Mori, Y., Deacu, E., Hamilton, J., Kan, T., Krasna, M.J., Beer, D.G., Pepe, M.S., Abraham, J.M., Feng, Z., Schmiegel, W., Greenwald, B.D., Meltzer, S.J. Oncogene (2005) [Pubmed]
  29. Role of Runx proteins in chondrogenesis. Yoshida, C.A., Komori, T. Crit. Rev. Eukaryot. Gene Expr. (2005) [Pubmed]
  30. Enhancer of zeste homologue 2 (EZH2) down-regulates RUNX3 by increasing histone H3 methylation. Fujii, S., Ito, K., Ito, Y., Ochiai, A. J. Biol. Chem. (2008) [Pubmed]
  31. Expression status of RUNX1/AML1 in normal gastric epithelium and its mutational analysis in microdissected gastric cancer cells. Usui, T., Aoyagi, K., Saeki, N., Nakanishi, Y., Kanai, Y., Ohki, M., Ogawa, K., Yoshida, T., Sasaki, H. Int. J. Oncol. (2006) [Pubmed]
  32. Phylogenesis and regulated expression of the RUNT domain transcription factors RUNX1 and RUNX3. Levanon, D., Glusman, G., Bettoun, D., Ben-Asher, E., Negreanu, V., Bernstein, Y., Harris-Cerruti, C., Brenner, O., Eilam, R., Lotem, J., Fainaru, O., Goldenberg, D., Pozner, A., Woolf, E., Xiao, C., Yarmus, M., Groner, Y. Blood Cells Mol. Dis. (2003) [Pubmed]
  33. An important role for RUNX3 in human L1 transcription and retrotransposition. Yang, N., Zhang, L., Zhang, Y., Kazazian, H.H. Nucleic Acids Res. (2003) [Pubmed]
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