A PHF19-YTHDC1 condensate switches EZH2-mediated gene suppression to activation for prostate cancer progression
Abstract
EZH2, a core component of PRC2 complex, silences global gene expression by tri-methylating histone H3K27. It remains an elusive question that EZH2 hyperexpression discords with its H3K27me3 activity of gene suppression in advanced prostate cancer. Here, we report a nascent RNA-dependent PHF19-YTHDC1 condensate capable of switching EZH2-mediated gene suppression to activation during prostate cancer progression. We found that the long isoform of PRC2 accessory subunit PHF19, PHF19L, was highly expressed in advanced prostate cancer that promoted the tumor progression and hormonal therapy resistance. Mechanistically, PHF19L was recruited to the m 6 A modified nascent RNA through YTHDC1 and formed a liquid-like YTHDC1-PHF19L condensate that pulled the EZH2 away from chromatin, resulting in reduced H3K27me3 deposition and the activated expression of EZH2-repressed genes. Therefore, our study reveals a biomolecular condensate that modulates the switch from EZH2-mediated epigenetic gene silence to activation during the progression of prostate cancer.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Shuai Yuan
State Key Laboratory of Coordination Chemistry, Key Laboratory of Mesoscopic Chemistry of MOE, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering
Dao-Jing Ming
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Jiapeng He
Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology
Meng-Yang Liu
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Shao-Hua He
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Hong Weng
Shu Xi
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Jin-Hui Zhang
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Ming-Hui Shi
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Jin-Long Cui
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Lu-Yao Li
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Haozhe Zhang
Chemical Sciences and Engineering Division
Dan-Qi Wang
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Fei Li
Meng-Meng Guo
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Yi Cai
Shi-Di Tang
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Shuang-Ying Wang
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Xing-Huan Wang
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Xian-Tao Zeng
Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University
Hailiang Hu
Department of Biochemistry, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology