Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets

作者：Haihong Qian, Min Zhu, Xinyu Tan, Yixing Zhang, Xiangning Liu, Li Yang · 发表于：Cell Death Discovery · 年份：2023 · DOI：10.1038/s41420-023-01775-6 · 被引用次数：98 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Ubiquitin and proteasome pathways

Transcriptional super-enhancers and the BET bromodomain protein BRD4 are emerging as critical drivers of tumorigenesis and therapeutic targets. Characterized by substantial accumulation of histone H3 lysine 27 acetylation (H3K27ac) signals at the loci of cell identity genes and critical oncogenes, super-enhancers are recognized, bound and activated by BRD4, resulting in considerable oncogene over-expression, malignant transformation, cancer cell proliferation, survival, tumor initiation and progression. Small molecule compound BRD4 BD1 and BD2 bromodomain inhibitors block BRD4 binding to super-enhancers, suppress oncogene transcription and expression, reduce cancer cell proliferation and survival, and repress tumor progression in a variety of cancer types. Like other targeted therapy agents, BRD4 inhibitors show moderate anticancer effects on their own, and exert synergistic anticancer effects in vitro and in preclinical models, when combined with other anticancer agents including CDK7 inhibitors, CBP/p300 inhibitors and histone deacetylase inhibitors. More recently, BRD4 BD2 bromodomain selective inhibitors, proteolysis-targeting chimera (PROTAC) BRD4 protein degraders, and dual BRD4 and CBP/p300 bromodomain co-inhibitors have been developed and shown better anticancer efficacy and/or safety profile. Importantly, more than a dozen BRD4 inhibitors have entered clinical trials in patients with cancer of various organ origins. In summary, super-enhancers and their reader BRD4 a...