Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer

Wenyu Wang (), Yen-An Tang, Qian Xiao, Wee Chyan Lee, Bing Cheng, Zhitong Niu, Gokce Oguz, Min Feng, Puay Leng Lee, Baojie Li, Zi-huan Yang, Yu-feng Chen, Ping Lan, Xiao-Jian Wu () and Qiang Yu ()
Additional contact information
Wenyu Wang: The Sixth Affiliated Hospital of Sun Yat-sen University
Yen-An Tang: Agency for Science, Technology, and Research
Qian Xiao: The Sixth Affiliated Hospital of Sun Yat-sen University
Wee Chyan Lee: Agency for Science, Technology, and Research
Bing Cheng: The Sixth Affiliated Hospital of Sun Yat-sen University
Zhitong Niu: The Sixth Affiliated Hospital of Sun Yat-sen University
Gokce Oguz: Agency for Science, Technology, and Research
Min Feng: Agency for Science, Technology, and Research
Puay Leng Lee: Agency for Science, Technology, and Research
Baojie Li: Ministry of Education, Shanghai Jiao Tong University
Zi-huan Yang: The Sixth Affiliated Hospital of Sun Yat-sen University
Yu-feng Chen: The Sixth Affiliated Hospital of Sun Yat-sen University
Ping Lan: The Sixth Affiliated Hospital of Sun Yat-sen University
Xiao-Jian Wu: The Sixth Affiliated Hospital of Sun Yat-sen University
Qiang Yu: Agency for Science, Technology, and Research

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-24687-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24687-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-24687-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().