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The MYC/BMI1 axis is essential for SETDB1-mediated breast tumorigenesis. (J Pathol, Jun 2018)

Xiao JF1, Sun QY1, Ding LW1, Chien W2, Liu XY1, Mayakanda 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
1 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
2 Division of Hematology/Oncology, Cedar-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
3 Department of Pathology, University of California, Los Angeles, USA.
4 Departments of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA.
5 Department of Biochemistry Yong Loo Lin School of Medicine, National University of Singapore.

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 protein expression via 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 confers a growth/self-renewal advantage to breast cancer cells. The activated c-MYC/BMI1 axis is essential for SETDB1-mediated breast tumorigenesis, because silencing either c-MYC or BMI1 profoundly abolishes the enhanced growth/colony formation conferred by SETDB1. Furthermore, c-MYC protein directly binds to the SETDB1 promoter region and enhances its transcription, suggesting a positive regulatory interplay occurs between SETDB1 and c-MYC. This study identified SETDB1 as a prominent oncogene and characterized the underlying mechanism of SETDB1 in driving breast cancer, and therefore provides a therapeutic rationale for targeting SETDB1/BMI1 signalling in breast cancer. This article is protected by copyright. All rights reserved.

KEYWORDS: SETDB1; breast cancer; c-MYC/BMI1 axis

PMID: 29926931