Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.
Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China.
Nat Commun. 2021 Jul 21;12(1):4441. doi: 10.1038/s41467-021-24687-4.
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 是一个 Bromodomain 和 Extraterminal（BET）蛋白家族成员，是一种很有前途的抗癌药物靶点。然而，针对 BRD4 的 BET 抑制剂在实体瘤中普遍存在耐药性。在这里，我们表明，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，导致结直肠癌细胞中 BRD4 酪氨酸 97/98 的磷酸化，导致 BRD4 稳定，这是由于与去泛素酶 UCHL3 的相互作用。BRD4 酪氨酸 97/98 的磷酸化也显示出与染色质的结合增加，但与 BET 抑制剂的结合减少，导致对 BET 抑制剂的耐药性。我们进一步表明，BRD4 磷酸化促进与 STAT3 的相互作用，通过与增强子和超级增强子的同时结合，诱导染色质重塑，支持促进肿瘤的转录程序。抑制 IL6/IL8-JAK2 信号会消除 BRD4 磷酸化，并在体外和体内增敏 BET 抑制剂。我们的研究揭示了 BRD4 激活和 BET 抑制剂耐药性的基质机制，为开发更有效地治疗 CRC 的策略提供了依据。
