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The work shows that PRC2i/EZH2i alone or with androgen receptor (AR) inhibitors triggers diverse cell state programs, increasing invasion, metastasis, and drug resistance while only modestly suppressing growth. Integrated genomics and epigenomics of patient-derived xenografts and clinical tumors reveal that PRC2/EZH2 normally suppresses cell state programs by maintaining chromatin bivalency. Hyperactive Wnt/β-catenin and PRC2/EZH2/AR perturbations alter bivalency via antagonism of PRC2 and feed-forward activation of MLL2/KMT2B, while REV-ERBα reprograms β-catenin to promote bivalency resolution and CSP expression. Dual Wnt/β-catenin and EZH2 targeting restores bivalency, diminishes diverse states, and blocks tumor growth, suggesting alternative strategies.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/targeting-wnt-catenin-and-circadian-regulator-restores-prc2ezh2-controlled-chromatin-bivalency-and-suppresses-cell-state-diversity/356724/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/targeting-wnt-catenin-and-circadian-regulator-restores-prc2ezh2-controlled-chromatin-bivalency-and-suppresses-cell-state-diversity/356724.png","ImageObject",300,407,{"name":92,"@type":93},"Sarah ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",14,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What effect do PRC2/EZH2 inhibitors have on cell state programs?","Question",{"text":113,"@type":114},"PRC2/EZH2 inhibitors, alone or combined with androgen receptor inhibitors, induce diverse cell state programs that can drive invasion, metastasis, and resistance to other drugs.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do PRC2/EZH2 suppress cell state program genes in tumors?",{"text":118,"@type":114},"PRC2/EZH2 suppresses cell state program genes by maintaining chromatin bivalency.",{"name":120,"@type":111,"acceptedAnswer":121},"Why does dual targeting of Wnt/β-catenin and EZH2 reduce tumor growth?",{"text":122,"@type":114},"Dual targeting restores chromatin bivalency, diminishes diverse cell states, and effectively blocks tumor growth.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},356724,1790185200,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},962085320529,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","The Journal of Clinical Investigation RESEAR CH ARTICLE  \nTargeting Wnt/β-catenin and circadian regulator restores PRC2/EZH2-controlled chromatin bivalency and suppresses cell state diversity  \nYatian Yang,1 Xiong Zhang,1 Varadha Balaji Venkadakrishnan,2,3 Hongye Zou,1 Xingling Zheng,1 Shiyao Guo,1 Christopher Z. Chen,4 Alexander D. Borowsky,5 Eva Corey,6 Ronald M. Evans,7 Allen C. Gao,8 Marc A. Dall’Era,8 Amina Zoubeidi,9,10 Primo N. Lara,11,12 Hsing-Jien Kung,1 Xinbin Chen,13 Himisha Beltran,2,3 and Hong-Wu Chen1,12,14  \n1Department of Biochemistry and Molecular Medicine, School of Medicine, UCD, Sacramento, California, USA. 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 3Harvard Medical School, Boston, Massachusetts, USA. 4Pharmaceutical Sciences and Pharmacogenomics (PSPG) Graduate Program, UCSF, San Francisco, California, USA. 5Department of Pathology and Laboratory Medicine, School of Medicine, UCD, Sacramento, California, USA. 6Department of Urology, University of Washington, Seattle, Washington, USA. 7Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. 8Department of Urologic Surgery, School of Medicine, UCD, Sacramento, California, USA. 9Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 10Vancouver Prostate Centre, Vancouver, British Columbia, Canada. 11Division of Hematology Oncology, Department of internal medicine, and 12Comprehensive Cancer Center, UCD, Sacramento, California, USA. 13Department of Surgical and Radiological Sciences, UCD, Davis, California, USA. 14US Veterans Affairs Northern California Health Care System-Mather, Mather, California, USA.  \nPRC2/EZH2 inhibitors (PRC2i/EZH2i) are promising for the treatment of advanced cancers including metastatic prostate cancer. Here, we show that PRC2i/EZH2i alone or in combination with androgen receptor (AR) inhibitors induced diverse cell state programs (CSPs) (e.g., response to stress or IFN, MYC targets, stem cells, EMT lineage plasticity, 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 patient-derived xenografts (PDXs) and clinical tumors revealed that PRC2/EZH2 suppressed CSP genes by maintaining chromatin bivalency. Hyperactive Wnt/β-catenin signaling and inhibitors of polycomb-repressive complex 2/enhancer of zeste homolog 2 (PRC2/EZH2) and theAR alter chromatin bivalency through antagonism of PRC2 and stimulation of MLL2/KMT2B in a feed-forward manner. The circadian rhythm regulator REV-ERBα unexpectedly reprogrammed β-catenin in promoting bivalency resolution and CSP gene expression. Dual targeting ofWnt/β-cateninand EZH2 diminished diverse cell states by restoring bivalency and effectively blocked tumor growth. Our findings provide unexpected insights into chromatin bivalency and dysregulated circadian rhythms in the control of cell state diversity and identify alternative therapeutic strategies that target PRC2/EZH2 for advanced malignancies.  \nIntroduction  \nThe polycomb-repressive complex 2 (PRC2) is a major epigenetic writer of the gene-silencing mark H3K27me3, with enhancer of zeste homolog 2 (EZH2) being its catalytic subunit and SUZ12, EED, and RBBP4/7 its core subunits (1, 2) . During embryonic development, the PRC2 complex plays an important role in cellfate transitions and differentiation through silencing of lineage-specific transcription factors (TFs) and other lineage-related gene programs. Most of those genes are comarked at the promoters with both transcriptionally active H3K4me3 and repressive H3K27me3 marks which are defined as chromatin bivalency and are “written”primarily by the methylases KMT2B (for H3K4me3) and EZH2/ PRC2 (3, 4) . Loss of PRC2 function leads to bival","cbCaif3qWSYd9CAp","https://ap.wps.com/l/cbCaif3qWSYd9CAp","pdf",17731284,18,"English","# Introduction\n## PRC2/EZH2 function in chromatin bivalency\n## Rationale for targeting PRC2/EZH2 in cancer and resistance mechanisms","[{\"question\":\"What effect do PRC2/EZH2 inhibitors have on cell state programs?\",\"answer\":\"PRC2/EZH2 inhibitors, alone or combined with androgen receptor inhibitors, induce diverse cell state programs that can drive invasion, metastasis, and resistance to other drugs.\"},{\"question\":\"How do PRC2/EZH2 suppress cell state program genes in tumors?\",\"answer\":\"PRC2/EZH2 suppresses cell state program genes by maintaining chromatin bivalency.\"},{\"question\":\"Why does dual targeting of Wnt/β-catenin and EZH2 reduce tumor growth?\",\"answer\":\"Dual targeting restores chromatin bivalency, diminishes diverse cell states, and effectively blocks tumor growth.\"}]","Targeting Wnt/β-catenin and circadian regulator restores PRC2/EZH2-controlled chromatin bivalency and suppresses cell state diversity | PDF",1790126938,45]