Targeting Wnt/β-Catenin and circadian regulator restores PRC2/EZH2 controlled chromatin bivalency and suppresses cell state diversity
Yatian Yang·Hong-Wu Chen·Hongye Zou·Allen C. Gao·Alexander D. Borowsky·Amina Zoubeidi·Marc Dall'Era·Xingling Zheng·Xiong Zhang·Shiyao Guo·Primo N. Lara·Christopher Z. Chen·Himisha Beltran·Hsing-Jien Kung·Ronald M. Evans·Xinbin Chen·Eva Corey·Varadha Balaji Venkadakrishnan
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 cur