Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-021-24687-4
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dc.titleStromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer
dc.contributor.authorWang, Wenyu
dc.contributor.authorTang, Yen-An
dc.contributor.authorXiao, Qian
dc.contributor.authorLee, Wee Chyan
dc.contributor.authorCheng, Bing
dc.contributor.authorNiu, Zhitong
dc.contributor.authorOguz, Gokce
dc.contributor.authorFeng, Min
dc.contributor.authorLee, Puay Leng
dc.contributor.authorLi, Baojie
dc.contributor.authorYang, Zi-huan
dc.contributor.authorChen, Yu-feng
dc.contributor.authorLan, Ping
dc.contributor.authorWu, Xiao-Jian
dc.contributor.authorYu, Qiang
dc.date.accessioned2022-10-13T06:44:16Z
dc.date.available2022-10-13T06:44:16Z
dc.date.issued2021-07-21
dc.identifier.citationWang, 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. https://doi.org/10.1038/s41467-021-24687-4
dc.identifier.issn2041-1723
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/233040
dc.description.abstractBRD4, 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).
dc.publisherNature Research
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceScopus OA2021
dc.typeArticle
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.description.doi10.1038/s41467-021-24687-4
dc.description.sourcetitleNature Communications
dc.description.volume12
dc.description.issue1
dc.description.page4441
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