2. Academic Validation
  3. Targeting Wnt/β-Catenin and circadian regulator restores PRC2/EZH2 controlled chromatin bivalency and suppresses cell state diversity

Targeting Wnt/β-Catenin and circadian regulator restores PRC2/EZH2 controlled chromatin bivalency and suppresses cell state diversity

  • J Clin Invest. 2026 Mar 17:e200260. doi: 10.1172/JCI200260.
Yatian Yang 1,  Xiong Zhang 1,  Varadha Balaji Venkadakrishnan 2,  Hongye Zou 1,  Xingling Zheng 1,  Shiyao Guo 1,  Christopher Z Chen 3,  Alexander D Borowsky 4,  Eva Corey 5,  Ronald M Evans 6,  Allen C Gao 7,  Marc A Dall'Era 7,  Amina Zoubeidi 8,  Primo N Lara 9,  Hsing-Jien Kung 1,  Xinbin Chen 10,  Himisha Beltran 2,  Hong-Wu Chen 1
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Medicine, UCD School of Medicine, Sacramento, United States of America.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States of America.
  • 3 Pharmaceutical Sciences and Pharmacogenomics Graduate Program, UCSF, San Francisco, United States of America.
  • 4 Department of Pathology and Laboratory Medicine, UCD School of Medicine, Sacramento, United States of America.
  • 5 Department of Urology, University of Washington, Seattle, United States of America.
  • 6 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, United States of America.
  • 7 Department of Urologic Surgery, UCD School of Medicine, Sacramento, United States of America.
  • 8 Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, Canada.
  • 9 Comprehensive Cancer Center, UCD School of Medicine, Sacramento, United States of America.
  • 10 Department of Surgery and Radiological Sciences, UCD School of Medicine, Sacramento, United States of America.
PMID: 41842971 DOI: 10.1172/JCI200260
Abstract

PRC2/EZH2 inhibitors (PRC2i/EZH2i) are promising for treatment of advanced cancers including metastatic prostate Cancer. Here we show that PRC2i/EZH2i alone or in combination with AR inhibitors induce diverse cell state programs (CSP) (e.g., response to stress or interferon, MYC targets, stem cell, EMT and multiple developmental programs) which led to increased tumor cell invasion, metastasis and resistance to Other drugs, in addition to modest suppression of tumor growth. In contrast to the current perception, our comprehensive, integrated genomics and epigenomics profiling of PDX and clinical tumors revealed that PRC2/EZH2 suppresses CSP genes through maintaining chromatin bivalency. Hyperactive Wnt/β-catenin signaling and inhibitors of PRC2/EZH2 and AR alter chromatin bivalency through antagonizing PRC2 and stimulating MLL2/KMT2B in a feedforward manner. Circadian rhythm regulator REV-ERBα unexpectedly reprograms β-catenin in promoting bivalency resolution and CSP gene expression. Dual targeting of Wnt/β-catenin and EZH2 diminishes diverse cell states through restoring bivalency and effectively block tumor growth. Our findings provide unexpected insights of chromatin bivalency and dysregulated circadian rhythm in control of cell state diversity and offer alternative therapeutic strategies targeting PRC2/EZH2 for advanced malignancies.

Keywords

Cell biology; Epigenetics; Genetics; Molecular biology; Oncology; Prostate cancer.

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