2. Academic Validation
  3. Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer

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

  • Nat Commun. 2021 Jul 21;12(1):4441. doi: 10.1038/s41467-021-24687-4.
Wenyu Wang  # 1 2 3,  Yen-An Tang  # 4 5,  Qian Xiao 6 7,  Wee Chyan Lee 4,  Bing Cheng 6 7,  Zhitong Niu 6 7,  Gokce Oguz 4,  Min Feng 4,  Puay Leng Lee 4,  Baojie Li 8,  Zi-Huan Yang 6 7,  Yu-Feng Chen 6 7 9,  Ping Lan 6 7 9,  Xiao-Jian Wu 10 11 12,  Qiang Yu 13 14 15
Affiliations

Affiliations

  • 1 Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China. wangwy63@mail.sysu.edu.cn.
  • 2 Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China. wangwy63@mail.sysu.edu.cn.
  • 3 Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore, 138672, Singapore. wangwy63@mail.sysu.edu.cn.
  • 4 Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore, 138672, Singapore.
  • 5 Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
  • 6 Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.
  • 7 Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.
  • 8 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 9 Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China.
  • 10 Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China. wuxjian@mail.sysu.edu.cn.
  • 11 Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China. wuxjian@mail.sysu.edu.cn.
  • 12 Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China. wuxjian@mail.sysu.edu.cn.
  • 13 Cancer Precision Medicine, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore, 138672, Singapore. yuq@gis.a-star.edu.sg.
  • 14 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. yuq@gis.a-star.edu.sg.
  • 15 Cancer and Stem Cell Biology, DUKE-NUS Graduate Medical School of Singapore, Singapore, 169857, Singapore. yuq@gis.a-star.edu.sg.
  • # Contributed equally.
PMID: 34290255 DOI: 10.1038/s41467-021-24687-4
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.

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