Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy.
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Nat Med. 2018 Oct;24(10):1599-1610. doi: 10.1038/s41591-018-0158-8. Epub 2018 Sep 17.
Cancer cells rely on dysregulated gene expression. This establishes specific transcriptional addictions that may be therapeutically exploited. Yet, the mechanisms that are ultimately responsible for these addictions are poorly understood. Here, we investigated the transcriptional dependencies of transformed cells to the transcription factors YAP and TAZ. YAP/TAZ physically engage the general coactivator bromodomain-containing protein 4 (BRD4), dictating the genome-wide association of BRD4 to chromatin. YAP/TAZ flag a large set of enhancers with super-enhancer-like functional properties. YAP/TAZ-bound enhancers mediate the recruitment of BRD4 and RNA polymerase II at YAP/TAZ-regulated promoters, boosting the expression of a host of growth-regulating genes. Treatment with small-molecule inhibitors of BRD4 blunts YAP/TAZ pro-tumorigenic activity in several cell or tissue contexts, causes the regression of pre-established, YAP/TAZ-addicted neoplastic lesions and reverts drug resistance. This work sheds light on essential mediators, mechanisms and genome-wide regulatory elements that are responsible for transcriptional addiction in cancer and lays the groundwork for a rational use of BET inhibitors according to YAP/TAZ biology.
癌细胞依赖失调的基因表达。这就形成了特定的转录成瘾，这些成瘾可能具有治疗潜力。然而，最终导致这些成瘾的机制还知之甚少。在这里，我们研究了转化细胞对转录因子 YAP 和 TAZ 的转录依赖性。YAP/TAZ 与一般共激活物溴结构域蛋白 4（BRD4）物理结合，决定了 BRD4 与染色质的全基因组关联。YAP/TAZ 标记了一大批具有超级增强子样功能特性的增强子。YAP/TAZ 结合的增强子介导 BRD4 和 RNA 聚合酶 II 在 YAP/TAZ 调节的启动子处的募集，从而增强了许多生长调节基因的表达。在几种细胞或组织环境中，用 BRD4 的小分子抑制剂处理会削弱 YAP/TAZ 的促肿瘤活性，导致已建立的、YAP/TAZ 成瘾性肿瘤病变的消退，并逆转耐药性。这项工作揭示了导致癌症转录成瘾的重要介质、机制和全基因组调节元件，并为根据 YAP/TAZ 生物学合理使用 BET 抑制剂奠定了基础。
