Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China.
UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Cancer Res. 2019 Mar 15;79(6):1191-1203. doi: 10.1158/0008-5472.CAN-18-3223. Epub 2019 Jan 23.
Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies. These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.
溴结构域和末端结构域（BET）家族蛋白，如 BRD4，是表观遗传读码器，可控制多种致癌蛋白的表达。靶向该家族蛋白最近已成为一种很有前途的抗癌方法。BET 抑制剂（BETi），无论是单独使用还是与其他抗癌药物联合使用，在多种肿瘤中均显示出疗效。然而，对 BETi 反应差异的分子机制尚不清楚。在这项研究中，我们报告称，死亡受体 5（DR5），外源性凋亡途径的关键组成部分，在结直肠癌细胞中对 BRD4 耗竭和 BETi 治疗有明显的诱导作用。BET 抑制后 DR5 的诱导是通过内质网应激和 CHOP 依赖性转录激活介导的。增强的 DR5 诱导对于 BETi 的化疗增敏和凋亡作用是必要的，并且在含有 speckle-type POZ protein (), BRD4 E3 泛素连接酶亚基突变的结直肠癌细胞中，增加了 BETi 的敏感性。在结直肠癌细胞异种移植模型中，BETi 联合化疗以 DR5 依赖性方式抑制肿瘤生长，并通过增强 DR5 诱导和凋亡，强烈抑制患者来源的异种移植肿瘤生长。这些发现表明，BETi 单独或联合化疗对结直肠癌有效，因为它增强了 DR5 的诱导和凋亡。DR5 诱导也可以作为设计个性化治疗和改善结直肠癌联合治疗的有用标记。这些发现揭示了 BET 抑制如何通过增强 DR5 诱导和凋亡来敏化化疗并杀死具有特定遗传改变的亚组结肠癌细胞，并可能为改善结肠癌治疗提供新的分子标记。
