Roles of RUNX3 as a tumor supressor protein

Abstract

Bone Morphogenetic Protein (BMPs), a member of the Transforming Growth Factor-beta (TGF-beta) superfamily, are multifunctional cytokines which regulate a broad spectrum of biological functions including development, morphogenesis, proliferation, differentiation and apoptosis. There is growing evidence that aberrations in BMP signalling play an important role in intestinal cancer pathogenesis. Recent studies show the presence of BMP receptor 1a mutations in juvenile polyposis and frequent Smad4 mutations in colon cancer. However, the exact molecular mechanisms remain poorly understood. The Runt domain transcription factor, RUNX3, is an integral component of signalling pathways mediated by both the TGF-beta and BMPs in various biological systems. RUNX3 has been shown to be a gastric tumour suppressor, functioning downstream of TGF-beta pathway. Recently we demonstrated the tumour suppressive effects of RUNX3 by its ability to attenuate beta-catenin/TCFs transactivation in intestinal tumorigenesis. The objective of this study is to explore the molecular basis of the tumour suppressive function of the BMP pathway through RUNX3 in colorectal carcinogenesis.I observed that BMP2/4 exerted a growth suppressive effect in HT-29, a human colorectal cancer cell line, which retains an intact BMP signalling pathway. c-Myc, a well-known oncogene in colorectal cancers and a target of the Wnt signalling pathway, was found to be down-regulated by BMP2/4 and/or RUNX3 in HT-29. Evidence obtained by this study suggests that up-regulation of RUNX3 by BMP reduces c-Myc expression. A mutational analysis of the human c-Myc promoter showed that RUNX3 reduces the promoter activity through RUNX- and TCF-consensus sites. Taken together, these results suggest that RUNX3 down-regulates c-Myc expression directly at the transcriptional level, and through attenuation of beta-catenin/TCFs, downstream of BMPs in colorectal epithelial cells.