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

Shuai Yuan1, Dao-Jing Ming1,2, Jiapeng He3

  • 1Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.

Proceedings of the National Academy of Sciences of the United States of America
|October 23, 2025
PubMed

Insights

A novel PHF19-YTHDC1 condensate switches EZH2 gene silencing to activation in advanced prostate cancer. This finding reveals a new mechanism driving tumor progression and hormonal therapy resistance.

Area of Science:

  • Epigenetics
  • Molecular Biology
  • Cancer Research

Background:

  • EZH2, a key part of the PRC2 complex, typically silences genes by modifying histone H3K27.
  • EZH2's role in gene suppression appears paradoxical in advanced prostate cancer despite its overexpression.

Purpose of the Study:

  • To investigate the mechanism behind EZH2's discordant activity in advanced prostate cancer.
  • To identify factors that switch EZH2-mediated gene suppression to activation during cancer progression.

Main Methods:

  • Analysis of PHF19 long isoform (PHF19L) expression in advanced prostate cancer.
  • Investigating the formation of PHF19-YTHDC1 condensates.
  • Assessing the impact of these condensates on EZH2 localization and H3K27me3 deposition.

Main Results:

  • PHF19L is highly expressed in advanced prostate cancer, promoting tumor progression and therapy resistance.
  • A YTHDC1-PHF19L condensate forms on m6A-modified nascent RNA.
  • This condensate sequesters EZH2 from chromatin, reducing H3K27me3 and activating repressed genes.

Conclusions:

  • A biomolecular condensate involving PHF19L and YTHDC1 switches EZH2 from gene silencing to activation.
  • This mechanism contributes to prostate cancer progression and hormonal therapy resistance.
  • Reveals a novel epigenetic regulatory mechanism in advanced prostate cancer.
Keywords:
EZH2YTHDC1liquid–liquid phase separationnascent RNAprostate cancer

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