A natural product targets BRD4 to inhibit phase separation and gene transcription
Cong Wang,
Huasong Lu,
Xiangzhong Liu,
Xiang Gao,
Wenjing Tian,
Haifeng Chen,
Yuhua Xue,
Qiang Zhou
Affiliations
Cong Wang
State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
Huasong Lu
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA; Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Xiangzhong Liu
State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
Xiang Gao
State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
Wenjing Tian
State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China
Haifeng Chen
State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China; Corresponding author
Yuhua Xue
State Key Laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiang'an South Road, Xiamen, Fujian 361102, China; Corresponding author
Qiang Zhou
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA; Corresponding author
Summary: The BET-bromodomain protein BRD4 uses two bromodomains to target acetyl-histones and other domains to recruit P-TEFb and other transcription factors to stimulate transcription of proto-oncogenes and key cell identity genes. Recent studies show that its ability to form phase-separated condensates that cluster preferentially at the super-enhancer regions of target genes is key for BRD4 to exert its functions. Here, we describe the identification of a natural product called PCG from polygonum cuspidatum Sieb.et Zucc., a traditional Chinese medicinal herb, that directly binds to BRD4. This binding inhibits BRD4 phase separation, turns dynamic BRD4 nuclear condensates into static aggregates, and effectively shuts down transcription of BRD4-dependent genes. Thus, through PCG we have discovered a BET inhibitor that not only selectively targets BRD4 but also works by suppressing phase separation, a mechanism of action that is different from those of the other known BET inhibitors.
