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The c-MYC-BMI1 axis is essential for SETDB1-mediated breast tumourigenesis. (J Pathol, Sep 2018)

Xiao JF1, Sun QY1, Ding LW1, Chien W2, Liu XY1, Mayakonda A1, Jiang YY1, Loh XY1, Ran XB1, Doan NB3, Castor B3, Chia D4, Said JW3, Tan KT1, Yang H1, Fu XY1,5, Lin DC2, Koeffler HP1,2.

Author information

1Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2Division of Hematology/Oncology, Cedar-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
3Department of Pathology, University of California, Los Angeles, CA, USA.
4Departments of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA.
5Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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.

PMID: 29926931