A PHF19-YTHDC1 condensate switches EZH2-mediated gene suppression to activation for prostate cancer progression.

IF 9.1 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Proceedings of the National Academy of Sciences of the United States of America Pub Date : 2025-10-23 DOI:10.1073/pnas.2510386122

Shuai Yuan,Dao-Jing Ming,Jiapeng He,Meng-Yang Liu,Shao-Hua He,Hong Weng,Shu Xi,Jin-Hui Zhang,Ming-Hui Shi,Jin-Long Cui,Lu-Yao Li,Haozhe Zhang,Dan-Qi Wang,Fei Li,Meng-Meng Guo,Yi Cai,Shi-Di Tang,Shuang-Ying Wang,Xing-Huan Wang,Xian-Tao Zeng,Hailiang Hu

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引用次数: 0

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 m6A 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.

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PHF19-YTHDC1凝聚物将ezh2介导的基因抑制转换为前列腺癌进展的激活。

EZH2是PRC2复合体的核心成分，通过三甲基化组蛋白H3K27来抑制全局基因的表达。在晚期前列腺癌中，EZH2高表达是否与其H3K27me3基因抑制活性不一致仍然是一个难以解决的问题。在这里，我们报道了一个新生的rna依赖性PHF19-YTHDC1凝聚物，能够在前列腺癌进展过程中将ezh2介导的基因抑制转换为激活。我们发现PRC2副亚基PHF19的长亚型PHF19L在晚期前列腺癌中高表达，促进肿瘤进展和激素治疗抵抗。机制上，PHF19L通过YTHDC1被募集到m6A修饰的新生RNA上，形成液体状的YTHDC1-PHF19L凝聚物，将EZH2从染色质上拉离，导致H3K27me3沉积减少，激活EZH2抑制基因的表达。因此，我们的研究揭示了一种生物分子凝聚物，在前列腺癌的进展过程中调节ezh2介导的表观遗传基因沉默到激活的转换。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Proceedings of the National Academy of Sciences of the United States of America 综合性期刊-综合性期刊

CiteScore

19.00

自引率

0.90%

发文量

3575

审稿时长

2.5 months

期刊介绍： The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.