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.
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DOI：
10.1038/s41467-021-24687-4
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发表时间：
2021-07-21
影响因子：
16.6
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Wang W;Tang YA;Xiao Q;Lee WC;Cheng B;Niu Z;Oguz G;Feng M;Lee PL;Li B;Yang ZH;Chen YF;Lan P;Wu XJ;Yu Q
BRD4是Bromodomain和Extraterminal （BET）蛋白家族成员，是一种很有前景的抗癌药物靶点。然而，针对BRD4的BET抑制剂的耐药在实体肿瘤中很常见。在这里，我们发现癌症相关成纤维细胞（CAF）激活的基质信号，白细胞介素-6/8- jak2，在结直肠癌中诱导BRD4在酪氨酸97/98位点磷酸化，由于与去泛素酶UCHL3相互作用，导致BRD4稳定。BRD4酪氨酸97/98位点的磷酸化也显示出与染色质结合增加，但与BET抑制剂结合减少，导致对BET抑制剂的抗性。我们进一步表明，BRD4磷酸化促进与STAT3相互作用，通过与增强子和超增强子的同时结合诱导染色质重塑，支持促进肿瘤的转录程序。在体外和体内，抑制IL6/IL8-JAK2信号通路可消除BRD4磷酸化并使BET抑制剂增敏。我们的研究揭示了BRD4激活和BET抑制剂耐药的基质机制，这为开发更有效治疗CRC的策略提供了理论依据。BRD4具有促肿瘤作用，但BRD4激活的非细胞自主机制有待阐明。在这里，作者揭示了CAFs通过IL6/IL8信号激活BRD4并诱导癌细胞对BET抑制剂产生抗性的机制。
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. BRD4 has a pro-tumorigenic role but non-cell-autonomous mechanisms of BRD4 activation need to be elucidated. Here the authors unravel a mechanism by which CAFs activate BRD4 and induce resistance to BET inhibitors in cancer cells through IL6/IL8 signaling.
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DOI：
10.1158/1078-0432.ccr-10-2694
发表时间：
2011-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Morikawa T;Baba Y;Yamauchi M;Kuchiba A;Nosho K;Shima K;Tanaka N;Huttenhower C;Frank DA;Fuchs CS;Ogino S
通讯作者：
Ogino S
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1126/science.aao2793
发表时间：
2018-05-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Muhar M;Ebert A;Neumann T;Umkehrer C;Jude J;Wieshofer C;Rescheneder P;Lipp JJ;Herzog VA;Reichholf B;Cisneros DA;Hoffmann T;Schlapansky MF;Bhat P;von Haeseler A;Köcher T;Obenauf AC;Popow J;Ameres SL;Zuber J
通讯作者：
Zuber J
DUB3 通过去泛素化 BRD4 促进 BET 抑制剂耐药性和癌症进展
影响因子：
16
作者：
Jin X;Yan Y;Wang D;Ding D;Ma T;Ye Z;Jimenez R;Wang L;Wu H;Huang H
通讯作者：
Huang H