Journal
JOURNAL OF PATHOLOGY
Volume 246, Issue 1, Pages 89-102Publisher
WILEY
DOI: 10.1002/path.5126
Keywords
SETDB1; c-MYC-BMI1 axis; breast cancer
Funding
- National Research Foundation Singapore under its Singapore Translational Research (STaR) Investigator Award [NMRC/STaR/0021/2014]
- NMRC Centre Grant
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiatives, an NCIS Yong Siew Yoon Research Grant
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Characterising the activated oncogenic signalling that leads to advanced breast cancer is of clinical importance. Here, we showed that SET domain, bifurcated 1 (SETDB1), a histone H3 lysine 9 methyltransferase, is aberrantly expressed and behaves as an oncogenic driver in breast cancer. SETDB1 enhances c-MYC and cyclin D1 expression by promoting the internal ribosome entry site (IRES)-mediated translation of MYC/CCND1 mRNA, resulting in prominent signalling of c-MYC to promote cell cycle progression, and provides a growth/self-renewal advantage to breast cancer cells. The activated c-MYC-BMI1 axis is essential for SETDB1-mediated breast tumorigenesis, because silencing of either c-MYC or BMI1 profoundly impairs the enhanced growth/colony formation conferred by SETDB1. Furthermore, c-MYC directly binds to the SETDB1 promoter region and enhances its transcription, suggesting a positive regulatory interplay between SETDB1 and c-MYC. In this study, we identified SETDB1 as a prominent oncogene and characterised the underlying mechanism whereby SETDB1 drives breast cancer, providing a therapeutic rationale for targeting SETDB1-BMI1 signalling in breast cancer. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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