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Title: Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer
Authors: Wang, Wenyu
Tang, Yen-An
Xiao, Qian
Lee, Wee Chyan
Cheng, Bing
Niu, Zhitong
Oguz, Gokce
Feng, Min
Lee, Puay Leng
Li, Baojie
Yang, Zi-huan
Chen, Yu-feng
Lan, Ping
Wu, Xiao-Jian
Yu, Qiang 
Issue Date: 21-Jul-2021
Publisher: Nature Research
Citation: Wang, Wenyu, Tang, Yen-An, Xiao, Qian, Lee, Wee Chyan, Cheng, Bing, Niu, Zhitong, Oguz, Gokce, Feng, Min, Lee, Puay Leng, Li, Baojie, Yang, Zi-huan, Chen, Yu-feng, Lan, Ping, Wu, Xiao-Jian, Yu, Qiang (2021-07-21). Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer. Nature Communications 12 (1) : 4441. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively. © 2021, The Author(s).
Source Title: Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-021-24687-4
Rights: Attribution 4.0 International
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