Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator

Jung Kim; Yongik Lee; Xiaodong Lu; Bing Song; Ka Wing Fong; Qi Cao; Jonathan D. Licht; Jonathan C. Zhao; Jindan Yu

doi:10.1016/j.celrep.2018.11.035

Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator

Jung Kim, Yongik Lee, Xiaodong Lu, Bing Song, Ka Wing Fong, Qi Cao, Jonathan D. Licht, Jonathan C. Zhao^*, Jindan Yu

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

206 Scopus citations

Abstract

Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively. Last, we demonstrate enhanced efficacy of enzymatic EZH2 inhibitors when used in combination with AR antagonists in blocking the dual roles of EZH2 and suppressing prostate cancer progression in vitro and in vivo. Taken together, our study reports EZH2 as a transcriptional activator, a key target of which is AR, and suggests a drug-combinatory approach to treat advanced prostate cancer. Kim et al. report EZH2 as a transcriptional activator that directly induces AR gene expression in a Polycomb- and methylation-independent manner, providing a mechanism to escape enzymatic EZH2 inhibitors. Combination of inhibitors with AR-targeted therapies showed a strong synergy in blocking the EZH2 downstream pathways and suppressing prostate cancer progression.

Original language	English (US)
Pages (from-to)	2808-2820.e4
Journal	Cell reports
Volume	25
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2018.11.035
State	Published - Dec 4 2018

Funding

We thank Dr. Ming Hu (Cleveland Clinic) for discussions regarding statistical analysis and Bin Zheng and Galina Gritsina for technical help. This work was supported in part by National Cancer Institute R01CA172384 (to J.Y.), P50CA180995 (pilot project, to J.Y.), and R50CA211271 (to J.C.Z.); American Cancer Society Research Scholar Award RSG-12-085-01 (to J.Y.); Department of Defense PC160328 (to J.Y.); and an institutional Ruth L. Kirschstein National Research Service award from the National Institute of Diabetes and Digestive and Kidney Diseases T32 DK007169 (to J.K.).

Keywords

AR antagonist enzalutamide
ChIP-seq
EPZ-6438
GSK126
androgen receptor inhibitor
enzymatic EZH2 inhibitor
epigenetic silencing
transcription activator

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2018.11.035

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title = "Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator",

abstract = "Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively. Last, we demonstrate enhanced efficacy of enzymatic EZH2 inhibitors when used in combination with AR antagonists in blocking the dual roles of EZH2 and suppressing prostate cancer progression in vitro and in vivo. Taken together, our study reports EZH2 as a transcriptional activator, a key target of which is AR, and suggests a drug-combinatory approach to treat advanced prostate cancer. Kim et al. report EZH2 as a transcriptional activator that directly induces AR gene expression in a Polycomb- and methylation-independent manner, providing a mechanism to escape enzymatic EZH2 inhibitors. Combination of inhibitors with AR-targeted therapies showed a strong synergy in blocking the EZH2 downstream pathways and suppressing prostate cancer progression.",

keywords = "AR antagonist enzalutamide, ChIP-seq, EPZ-6438, GSK126, androgen receptor inhibitor, enzymatic EZH2 inhibitor, epigenetic silencing, transcription activator",

author = "Jung Kim and Yongik Lee and Xiaodong Lu and Bing Song and Fong, {Ka Wing} and Qi Cao and Licht, {Jonathan D.} and Zhao, {Jonathan C.} and Jindan Yu",

note = "Funding Information: We thank Dr. Ming Hu (Cleveland Clinic) for discussions regarding statistical analysis and Bin Zheng and Galina Gritsina for technical help. This work was supported in part by National Cancer Institute R01CA172384 (to J.Y.), P50CA180995 (pilot project, to J.Y.), and R50CA211271 (to J.C.Z.); American Cancer Society Research Scholar Award RSG-12-085-01 (to J.Y.); Department of Defense PC160328 (to J.Y.); and an institutional Ruth L. Kirschstein National Research Service award from the National Institute of Diabetes and Digestive and Kidney Diseases T32 DK007169 (to J.K.). Publisher Copyright: {\textcopyright} 2018 The Authors",

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T1 - Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator

AU - Kim, Jung

AU - Lee, Yongik

AU - Lu, Xiaodong

AU - Song, Bing

AU - Fong, Ka Wing

AU - Cao, Qi

AU - Licht, Jonathan D.

AU - Zhao, Jonathan C.

AU - Yu, Jindan

N1 - Funding Information: We thank Dr. Ming Hu (Cleveland Clinic) for discussions regarding statistical analysis and Bin Zheng and Galina Gritsina for technical help. This work was supported in part by National Cancer Institute R01CA172384 (to J.Y.), P50CA180995 (pilot project, to J.Y.), and R50CA211271 (to J.C.Z.); American Cancer Society Research Scholar Award RSG-12-085-01 (to J.Y.); Department of Defense PC160328 (to J.Y.); and an institutional Ruth L. Kirschstein National Research Service award from the National Institute of Diabetes and Digestive and Kidney Diseases T32 DK007169 (to J.K.). Publisher Copyright: © 2018 The Authors

PY - 2018/12/4

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N2 - Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively. Last, we demonstrate enhanced efficacy of enzymatic EZH2 inhibitors when used in combination with AR antagonists in blocking the dual roles of EZH2 and suppressing prostate cancer progression in vitro and in vivo. Taken together, our study reports EZH2 as a transcriptional activator, a key target of which is AR, and suggests a drug-combinatory approach to treat advanced prostate cancer. Kim et al. report EZH2 as a transcriptional activator that directly induces AR gene expression in a Polycomb- and methylation-independent manner, providing a mechanism to escape enzymatic EZH2 inhibitors. Combination of inhibitors with AR-targeted therapies showed a strong synergy in blocking the EZH2 downstream pathways and suppressing prostate cancer progression.

AB - Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively. Last, we demonstrate enhanced efficacy of enzymatic EZH2 inhibitors when used in combination with AR antagonists in blocking the dual roles of EZH2 and suppressing prostate cancer progression in vitro and in vivo. Taken together, our study reports EZH2 as a transcriptional activator, a key target of which is AR, and suggests a drug-combinatory approach to treat advanced prostate cancer. Kim et al. report EZH2 as a transcriptional activator that directly induces AR gene expression in a Polycomb- and methylation-independent manner, providing a mechanism to escape enzymatic EZH2 inhibitors. Combination of inhibitors with AR-targeted therapies showed a strong synergy in blocking the EZH2 downstream pathways and suppressing prostate cancer progression.

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KW - ChIP-seq

KW - EPZ-6438

KW - GSK126

KW - androgen receptor inhibitor

KW - enzymatic EZH2 inhibitor

KW - epigenetic silencing

KW - transcription activator

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AN - SCOPUS:85057460765

SN - 2211-1247

VL - 25

SP - 2808-2820.e4

JO - Cell reports

JF - Cell reports

IS - 10

ER -

Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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