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 4

Cotargeting of PRC2 and AR effectively disrupts the functional balance of PRC2 and KMT2B in bivalency maintenance.

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Cotargeting of PRC2 and AR effectively disrupts the functional balance o...
(A) Heatmaps and signal profiles of H3K27me3 and H3K4me3 ChIP-seq signal intensity within ±3 kb windows at the TSS of CSPs (n = 798 peaks) in LuCaP35CR tumors in mice treated as indicated for 10 days. The ChIP-seq peaks were selected with FDR below 0.05. (B) IGV snapshots of H3K27me3 and H3K4me3 ChIP-seq peaks at representative CSP genes in LuCaP35CR tumors in mice treated as indicated for 10 days. (C) Venn diagram of ChIP-seq peak overlaps between EZH2 and EED at bivalent promoters in LuCaP35CR tumors. (D) Signal profiles of EZH2 and EED ChIP-seq within ±3 kb windows around the TSS at bivalent genes in LuCaP35CR and Myc-CaP tumors in mice treated as indicated for 10 days. The ChIP-seq peak was selected with a FDR of less than 0.05. (E) Signal profiles of EZH2, H3K27me3, and H3K4me3 ChIP-seq signal intensity within ±3 kb windows at the TSS at canonical but nonbivalent PRC2 target genes and at bivalent genes in 42DEnzR cells treated with 10 μM Taz or vehicle for 24 hours. (F) Heatmaps of gene expression changes when compared with vehicle in 42DEnzR cells treated as indicated for 48 hours. (G) Signal profiles of KMT2B ChIP-seq signal intensity within ±3 kb windows at the TSS at all bivalent gene promoters in LuCaP 35CR tumors and MyC-CaP mouse tumors treated as indicated for 10 days. (H) Western blots of proteins in LNCaP cells treated as indicated for 72 hours.