The c‐MYC–BMI1 axis is essential for SETDB1‐mediated breast tumourigenesis

Abstract 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 tumourigenesis, 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 © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.