Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer [ChIP-seq]. Tumor Microenvironment-induced BRD4 Activation Results in Chromatin Remodeling and Therapy Resistance in Colorectal Cancer [ChIP-seq]

Tumor microenvironment promotes tumorigenesis, but its role in modulating tumor chromatin activity is poorly understood. Here, we show that inflammatory cytokines interleukin-6 and -8 in the tumor microenvironment induces JAK2-mediated phosphorylation of bromodomain-containing protein 4 (BRD4), which results in interaction with UCHL3 deubiquitinase, leading to increased BRD4 protein stabilization in colorectal cancer. JAK2-phosphorylated BRD4 shows enhanced activity binding to chromatin but reduced binding to BRD4 inhibitors, leading to treatment resistance. Moreover, BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Thus, the inflammatory tumor microenvironment provides a powerful mechanism for tumor chromatin remodeling and oncogenic transcription, which suggests a unrecognized new strategy to enhance BRD4 inhibitor response. Overall design: Examination of 4 differents transcription/epigenetic regulators in patient-derived colorectal cancer cells with/without IL6/8 treatment.

肿瘤微环境（tumor microenvironment）可促进肿瘤发生，但其调控肿瘤染色质活性的功能尚未完全阐明。本研究发现，肿瘤微环境中的炎性细胞因子白细胞介素-6（interleukin-6）与白细胞介素-8（interleukin-8）可诱导Janus激酶2（Janus kinase 2, JAK2）介导的含溴结构域蛋白4（bromodomain-containing protein 4, BRD4）发生磷酸化，使其与去泛素化酶UCHL3（ubiquitin carboxyl-terminal hydrolase L3）结合，进而提升结直肠癌（colorectal cancer）细胞中BRD4的蛋白稳定性。经JAK2磷酸化的BRD4与染色质的结合活性增强，但与BRD4抑制剂（BRD4 inhibitor）的结合能力降低，最终导致治疗耐药。此外，BRD4磷酸化可促进其与信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3）结合，通过同时结合增强子（enhancers）与超级增强子（super-enhancers）诱导染色质重塑，从而支撑促肿瘤转录程序。综上，炎性肿瘤微环境为肿瘤染色质重塑与致癌转录提供了关键机制，这为增强BRD4抑制剂的应答效果提供了此前未被认知的全新策略。实验设计：对经/未经白细胞介素-6/8处理的患者来源结直肠癌细胞中的4种转录/表观遗传调控因子进行检测分析。