Bone morphogenetic proteins (BMPs), members of the
transforming growth factor-beta (
TGF-beta) superfamily, are multifunctional
cytokines regulating a broad spectrum of
biological functions. Recent studies show the presence of
BMP receptor 1a mutations in juvenile polyposis and frequent Smad4 mutations in
colon cancer, suggesting that aberrations in BMP signaling play an important role in
intestinal cancer pathogenesis. However, the exact molecular mechanisms remain poorly understood. The Runt domain
transcription factor RUNX3 is an integral component of signaling pathways mediated by
TGF-beta and BMPs. RUNX3 is a gastric and colon
tumor suppressor, functioning downstream of
TGF-beta. Recently, we showed the
tumor-suppressive effects of RUNX3 by its ability to attenuate
beta-catenin/
T-cell factors (TCFs) transactivation in intestinal
tumorigenesis. Here, we explore the molecular basis of the
tumor-suppressive function of the BMP pathway through RUNX3 in colorectal
carcinogenesis. BMP exerted a growth-suppressive effect in HT-29, a human
colorectal cancer cell line. c-Myc oncogene was found to be downregulated by BMP and/or RUNX3. We show that upregulation of RUNX3 by BMP reduces c-Myc expression. Evidence is presented suggesting that RUNX3 downregulates c-Myc expression by two parallel pathways-directly at the transcriptional level and through attenuation of
beta-catenin/TCFs, downstream of BMPs in
colorectal cancer cells.