TY - JOUR
T1 - Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer
AU - Wang, Wenyu
AU - Tang, Yen An
AU - Xiao, Qian
AU - Lee, Wee Chyan
AU - Cheng, Bing
AU - Niu, Zhitong
AU - Oguz, Gokce
AU - Feng, Min
AU - Lee, Puay Leng
AU - Li, Baojie
AU - Yang, Zi huan
AU - Chen, Yu feng
AU - Lan, Ping
AU - Wu, Xiao Jian
AU - Yu, Qiang
N1 - Funding Information:
This work was supported by the core funding of the Agency for Science, Technology, and Research of Singapore (to Q.Y.), the National Natural Science Foundation of China (81972818, to W.W.; 82003163, to B.C.; and 81972212, to X.J.W.), the Fundamental Research Funds for the Central Universities, Sun Yat-sen University (20ykzd01, to W. W.), the Key-Area Research and Development Program of Guangdong Province (2019B020229002, to P.L.), the Science & Technology Program of Guangdong Province (2021A0505030028, to X.J.W.). We thank the Histopathology Department from the Institute of Molecular and Cell Biology, Agency for Science, Technology and Research of Singapore (A*STAR), for their service in IHC staining and analysis. The authors would like to thank the support from the National Key Clinical Discipline of China.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-24687-4
DO - 10.1038/s41467-021-24687-4
M3 - Article
C2 - 34290255
AN - SCOPUS:85111104301
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4441
ER -