SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways

Huairui Yuan; Ying Han; Xuege Wang; Ni Li; Qiuli Liu; Yuye Yin; Hanling Wang; Lulu Pan; Li Li; Kun Song; Tong Qiu; Qiang Pan; Qilong Chen; Guoying Zhang; Yi Zang; Minjia Tan; Jian Zhang; Qintong Li; Xiaoming Wang; Jun Jiang; Jun Qin

doi:10.1016/j.ccell.2020.05.022

SETD2 Restricts Prostate Cancer Metastasis by Integrating EZH2 and AMPK Signaling Pathways

Cancer Cell. 2020 Sep 14;38(3):350-365.e7. doi: 10.1016/j.ccell.2020.05.022. Epub 2020 Jul 2.

Authors

Huairui Yuan¹, Ying Han¹, Xuege Wang¹, Ni Li¹, Qiuli Liu², Yuye Yin³, Hanling Wang¹, Lulu Pan⁴, Li Li⁵, Kun Song⁶, Tong Qiu⁷, Qiang Pan¹, Qilong Chen¹, Guoying Zhang¹, Yi Zang¹, Minjia Tan⁴, Jian Zhang⁶, Qintong Li⁷, Xiaoming Wang⁸, Jun Jiang⁹, Jun Qin¹⁰

Affiliations

¹ CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
² Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.
³ Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, NHC Key Laboratory of Antibody Technique, Department of Microbes and Infection, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁵ State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai 200127, China.
⁶ State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
⁷ Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 20 Renmin South Road, Chengdu 610041, China.
⁸ Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, NHC Key Laboratory of Antibody Technique, Department of Microbes and Infection, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China. Electronic address: xmwang@njmu.edu.cn.
⁹ Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China. Electronic address: jiangjun_64@163.com.
¹⁰ CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China. Electronic address: qinjun@sibs.ac.cn.

PMID: 32619406
DOI: 10.1016/j.ccell.2020.05.022

Abstract

The level of SETD2-mediated H3K36me3 is inversely correlated with that of EZH2-catalyzed H3K27me3. Nevertheless, it remains unclear whether these two enzymatic activities are molecularly intertwined. Here, we report that SETD2 delays prostate cancer (PCa) metastasis via its substrate EZH2. We show that SETD2 methylates EZH2 which promotes EZH2 degradation. SETD2 deficiency induces a Polycomb-repressive chromatin state that enables cells to acquire metastatic traits. Conversely, mice harboring nonmethylated EZH2 mutant or SETD2 mutant defective in binding to EZH2 develop metastatic PCa. Furthermore, we identify that metformin-stimulated AMPK signaling converges at FOXO3 to stimulate SETD2 expression. Together, our results demonstrate that the SETD2-EZH2 axis integrates metabolic and epigenetic signaling to restrict PCa metastasis.

Keywords: AMPK; EZH2; SETD2; epigenetic and metabolic dysregulations; metformin; prostate cancer metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / genetics*
AMP-Activated Protein Kinases / metabolism
Animals
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein / genetics*
Enhancer of Zeste Homolog 2 Protein / metabolism
Gene Expression Regulation, Neoplastic*
Histone-Lysine N-Methyltransferase / genetics*
Histone-Lysine N-Methyltransferase / metabolism
Humans
Kaplan-Meier Estimate
Male
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, Nude
Mice, SCID
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Signal Transduction / genetics*
Transplantation, Heterologous

Substances

EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Histone-Lysine N-Methyltransferase
SETD2 protein, human
AMP-Activated Protein Kinases