Fan Pengyu, Shang Xue-Ying, Song Aixia, Chen Shuo, Mao Run-Yuan, Ma Jingchuan, Chen Jiwei, Wang Zhenning, Zheng Hai, Tao Bolin, Hong Lei, Liu Jiaxian, Xu Wei, Jiang Wei, Shen Hongjie, Zhang Qi, Yang Huijuan, Meng Xiao-Ming, Lan Fei, Cheng Jingdong, Xu Congling, Zhang Peng, Jiang Hai, Chen Fei Xavier
Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
Nat Chem Biol. 2025 Jan 14. doi: 10.1038/s41589-024-01807-x.
Chromatin and transcription regulators are critical to defining cell identity through shaping epigenetic and transcriptional landscapes, with their misregulation being closely linked to oncogenesis. Pharmacologically targeting these regulators, particularly the transcription-activating BET proteins, has emerged as a promising approach in cancer therapy, yet intrinsic or acquired resistance frequently occurs, with poorly understood mechanisms. Here, using genome-wide CRISPR screens, we find that BET inhibitor efficacy in mediating transcriptional silencing and growth inhibition depends on the auxiliary/arm/tail module of the Integrator-PP2A complex (INTAC), a global regulator of RNA polymerase II pause-release dynamics. This process bypasses a requirement for the catalytic activities of INTAC and instead leverages direct engagement of the auxiliary module with the RACK7/ZMYND8-KDM5C complex to remove histone H3K4 methylation. Targeted degradation of the COMPASS subunit WDR5 to attenuate H3K4 methylation restores sensitivity to BET inhibitors, highlighting how simultaneously targeting coordinated chromatin and transcription regulators can circumvent drug-resistant tumors.
染色质和转录调节因子对于通过塑造表观遗传和转录格局来定义细胞身份至关重要，它们的失调与肿瘤发生密切相关。从药理学角度靶向这些调节因子，尤其是转录激活的BET蛋白，已成为癌症治疗中一种有前景的方法，但内在或获得性耐药经常发生，其机制尚不清楚。在这里，我们使用全基因组CRISPR筛选发现，BET抑制剂在介导转录沉默和生长抑制方面的功效取决于整合酶-PP2A复合物（INTAC）的辅助/臂/尾模块，INTAC是RNA聚合酶II暂停释放动力学的全局调节因子。这个过程绕过了对INTAC催化活性的需求，而是利用辅助模块与RACK7/ZMYND8-KDM5C复合物的直接结合来去除组蛋白H3K4甲基化。靶向降解COMPASS亚基WDR5以减弱H3K4甲基化可恢复对BET抑制剂的敏感性，突出了同时靶向协调的染色质和转录调节因子如何能够规避耐药肿瘤。
