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

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.