Spatially constrained tandem bromodomain inhibition bolsters sustained repression of BRD4 transcriptional activity for TNBC cell growth
Abstract
BRD4, a major BET family protein, regulates gene transcription through coordinated binding of its characteristic tandem bromodomains (BrDs) to lysine-acetylated histones and transcription factors. Studies show that BRD4 function in transcriptional regulation is likely context- and cell-type-dependent, consistent with the observation that pan-BET BrD inhibitors such as JQ1 are much less effective in solid tumors than in hematopoietic cancers. Here, we show that spatially constrained bivalent inhibition of BRD4 BrDs with our BET inhibitor MS645 results in a sustained repression of BRD4 transcriptional activity in solid-tumor cells including triple-negative breast cancer (TNBC) cells. Our study offers a therapeutic strategy to maximally control BRD4 activity required for rapid cell proliferation of the devastating TNBC that lacks targeted therapy.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 16, 2018
- Source ID
- 10.1073/pnas.1720000115
Entities
People
- Chunyan Ren
- Donglei Ji
- Fan Zhang
- Fangbin Han
- Guangtao Zhang
- Jamel Meslamani
- Ka-lung Cheung
- Lei Zeng
- Lingling Cao
- Martin J. Walsh
- Ming-Ming Zhou
- Nicolas Babault
- Qian Zhou
- Qiang Zhang
- Rajal Sharma
- Shibo Fu
- Weijia Zhang
- Yaoyao Xu
- Yingdi Cao
- Zhengzi Yi
Organizations
- Icahn School of Medicine at Mount Sinai
- Jilin University
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- United States Department of Defense