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 5

Wnt/β-catenin signaling drives chromatin bivalency changes.

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Wnt/β-catenin signaling drives chromatin bivalency changes. (A) Chromati...
(A) Chromatin state analysis by ChromHMM of C4-2B cells with 9 epigenetic and TF ChIP-seq marks. Blue shadings depict the average intensity of a particular mark across each chromatin state. (B) Venn diagram of genes with β-catenin ChIP-seq peaks at promoters and bivalent genes in C4-2B cells. (C and D) Signal profiles and heatmaps of β-catenin (C) and H3K4me3 and H3K27me3 (D) ChIP-seq signal intensities within ±3 kb windows around the TSS at bivalent promoters in C4-2B cells with ca–β-C expression or vector control, or in C4-2B cells treated with 10 μM LGK974 or vehicle for 24 hours. (E) IGV snapshots of β-catenin ChIP-seq at the indicated bivalent genes in C4-2B cells treated as in D. (F) Volcano plots of FCs in log2 of H3K27me3 (left) and H3K4me3 (right) at all bivalent promoters in C4-2B cells treated with 10 μM LGK974 for 24 hours and their associated P values (–log10). (G) GSEA of gene expression changes detected by RNA-seq in C4-2B cells treated with 10 μM LGK974 or siβ-catenin for 48 hours, or with ca–β-C expression.