Targeting Wnt/β-catenin and circadian regulator restores PRC2/EZH2-controlled chromatin bivalency and suppresses cell...

Area of Science:

• Epigenetics
• Cancer Biology
• Chromatin Biology

Background:

• Polycomb repressive complex 2 inhibitors (PRC2i/EZH2i) show promise for treating advanced cancers, including metastatic prostate cancer.
• Current understanding suggests PRC2/EZH2 primarily suppresses gene expression, but its role in diverse cell state programs (CSPs) is complex.

Purpose of the Study:

• To investigate the effects of PRC2/EZH2 inhibitors (PRC2i/EZH2i) alone or with androgen receptor (AR) inhibitors on cancer cell states.
• To elucidate the mechanisms by which PRC2/EZH2 regulates CSPs and chromatin bivalency.
• To explore novel therapeutic strategies targeting PRC2/EZH2 and Wnt/β-catenin signaling.

Main Methods:

• Integrated genomics and epigenomics profiling of patient-derived xenografts (PDX) and clinical tumors.
• Analysis of cell state programs, including stress response, interferon response, MYC targets, stem cell, epithelial-mesenchymal transition (EMT), and developmental programs.
• Investigating the roles of Wnt/β-catenin signaling, MLL2/KMT2B, and circadian rhythm regulator REV-ERBα in chromatin bivalency and CSPs.

Main Results:

• PRC2i/EZH2i alone or with AR inhibitors induced diverse CSPs, leading to increased invasion, metastasis, and drug resistance.
• PRC2/EZH2 was found to suppress CSP genes by maintaining chromatin bivalency, contrary to previous perceptions.
• Hyperactive Wnt/β-catenin signaling and PRC2i/EZH2i/AR inhibitors altered chromatin bivalency by antagonizing PRC2 and stimulating MLL2/KMT2B.
• REV-ERBα reprogrammed β-catenin to promote bivalency resolution and CSP gene expression.
• Dual targeting of Wnt/β-catenin and EZH2 restored bivalency, diminished diverse cell states, and effectively blocked tumor growth.

Conclusions:

• PRC2/EZH2 plays a critical role in suppressing diverse cell state programs through chromatin bivalency.
• Dysregulated circadian rhythm and Wnt/β-catenin signaling contribute to altered cell state diversity.
• Dual inhibition of Wnt/β-catenin and EZH2 represents a promising therapeutic strategy for advanced malignancies by restoring chromatin bivalency and blocking tumor growth.