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Published on: September 1, 2019
Role of RUNX3 in bone morphogenetic protein signaling in colorectal cancer
Cecilia Wei Lin Lee1, Kosei Ito, Yoshiaki Ito
1Cancer Science Institute of Singapore and NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
Abstract:
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.
Insights
Bone morphogenetic proteins (BMPs) suppress colorectal cancer growth by upregulating RUNX3, which inhibits the c-Myc oncogene. This pathway involves RUNX3 directly reducing c-Myc and indirectly through beta-catenin signaling.
Area of Science:
- Molecular biology
- Cancer research
- Cell signaling
Background:
- Bone morphogenetic proteins (BMPs) are crucial signaling molecules in the transforming growth factor-beta (TGF-beta) superfamily.
- Aberrations in BMP signaling pathways are implicated in intestinal cancer, with mutations found in BMP receptor 1a and Smad4.
- RUNX3, a tumor suppressor, acts downstream of TGF-beta and BMP signaling, modulating beta-catenin/T-cell factor (TCF) activity.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the tumor-suppressive function of the BMP pathway via RUNX3 in colorectal carcinogenesis.
- To elucidate how BMP signaling impacts colorectal cancer cell growth and oncogene expression.
Main Methods:
- Utilized the human colorectal cancer cell line HT-29.
- Assessed the effects of BMP and RUNX3 on cell growth and c-Myc oncogene expression.
- Investigated the regulatory role of RUNX3 in c-Myc expression through transcriptional and beta-catenin/TCF pathways.
Main Results:
- BMP demonstrated a significant growth-suppressive effect on HT-29 colorectal cancer cells.
- BMP and/or RUNX3 were found to downregulate the expression of the c-Myc oncogene.
- Upregulation of RUNX3 by BMP led to reduced c-Myc expression, mediated by direct transcriptional inhibition and attenuation of beta-catenin/TCF signaling.
Conclusions:
- The BMP pathway, through RUNX3, exerts tumor-suppressive effects in colorectal cancer.
- RUNX3 inhibits colorectal cancer progression by downregulating c-Myc expression via multiple mechanisms.
- Targeting the BMP/RUNX3/c-Myc axis presents a potential therapeutic strategy for colorectal cancer.
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