Targeting Wnt/β-Catenin and circadian regulator restores PRC2/EZH2 controlled chromatin bivalency and suppresses cell state diversity - PubMed
4 hours ago
- #chromatin bivalency
- #PRC2/EZH2 inhibitors
- #circadian rhythm
- PRC2/EZH2 inhibitors (PRC2i/EZH2i) show promise in treating advanced cancers, including metastatic prostate cancer.
- PRC2i/EZH2i, alone or combined with AR inhibitors, induce diverse cell state programs (CSP), leading to increased tumor cell invasion, metastasis, and drug resistance.
- PRC2/EZH2 suppresses CSP genes by maintaining chromatin bivalency, contrary to current perceptions.
- Hyperactive Wnt/β-catenin signaling and PRC2/EZH2 inhibitors alter chromatin bivalency by antagonizing PRC2 and stimulating MLL2/KMT2B.
- Circadian rhythm regulator REV-ERBα reprograms β-catenin to promote bivalency resolution and CSP gene expression.
- Dual targeting of Wnt/β-catenin and EZH2 restores bivalency, diminishes diverse cell states, and effectively blocks tumor growth.
- Findings offer new insights into chromatin bivalency and circadian rhythm dysregulation in controlling cell state diversity, suggesting alternative therapeutic strategies for advanced malignancies.