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

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

Abstract

PRC2/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 the AR 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 of Wnt/β-catenin and 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.

Authors

Yatian Yang, Xiong Zhang, Varadha Balaji Venkadakrishnan, Hongye Zou, Xingling Zheng, Shiyao Guo, Christopher Z. Chen, Alexander D. Borowsky, Eva Corey, Ronald M. Evans, Allen C. Gao, Marc A. Dall’Era, Amina Zoubeidi, Primo N. Lara, Hsing-Jien Kung, Xinbin Chen, Himisha Beltran, Hong-Wu Chen

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Figure 8

Induction of tumor cell–state diversity by PRC2/EZH2 inhibition can be mitigated by Wnt/β-catenin signaling blockade through alteration of chromatin bivalency.

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Induction of tumor cell–state diversity by PRC2/EZH2 inhibition can be m...
(A) Heatmaps of the GSVA score of the indicated programs detected by RNA-seq in LuCaP35CR tumors in mice treated as indicated for 10 days. (B) Representative confocal microscopy images of LP protein expression in LuCaP35CR tumors in mice treated as indicated (n = 5 mice per group). Note: The experiment here shares samples of vehicle and Taz treatments with those in Figure 2C and Supplemental Figure 2H. Scale bars: 50 μm. Bar graphs display ImageJ-analyzed IF intensity from 7 randomly selected fields per tumor. ****P < 0.0001, by 2-tailed Student’s t test. (C) Growth curves of LuCaP35CR PDX and MyC-CaP CR tumors in mice treated with vehicle or the indicated compounds for the indicated durations, 7 times per week (n = 5 mice per group). **P < 0.01 and ***P < 0.001, by 2-tailed Student’s t test. (D) Signal profiles and heatmaps of the indicated histone marks at bivalent promoters in LuCaP35CR tumors in mice treated as indicated for 10 days. (E) Signal profiles of EZH2, EED, and KMT2B/MLL2 ChIP-seq within ±3 kb windows around the TSS at bivalent CSPs in LuCaP35CR and MyC-CaP CR tumors in mice treated as indicated for 10 days.