Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function

Lixin Wan; Kexin Xu; Yongkun Wei; Jinfang Zhang; Tao Han; Christopher Fry; Zhao Zhang; Yao Vickie Wang; Liyu Huang; Min Yuan; Weiya Xia; Wei-Chao Chang; Wen-Chien Huang; Chien-Liang Liu; Yuan-Ching Chang; Jinsong Liu; Yun Wu; Victor X Jin; Xiangpeng Dai; Jianfeng Guo; Jia Liu; Shulong Jiang; Jin Li; John M Asara; Myles Brown; Mien-Chie Hung; Wenyi Wei

doi:10.1016/j.molcel.2017.12.024

Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function

Mol Cell. 2018 Jan 18;69(2):279-291.e5. doi: 10.1016/j.molcel.2017.12.024.

Authors

Lixin Wan¹, Kexin Xu², Yongkun Wei³, Jinfang Zhang⁴, Tao Han⁵, Christopher Fry⁶, Zhao Zhang⁷, Yao Vickie Wang⁷, Liyu Huang⁸, Min Yuan⁹, Weiya Xia³, Wei-Chao Chang¹⁰, Wen-Chien Huang¹¹, Chien-Liang Liu¹¹, Yuan-Ching Chang¹¹, Jinsong Liu¹², Yun Wu¹², Victor X Jin⁷, Xiangpeng Dai⁴, Jianfeng Guo¹³, Jia Liu¹⁴, Shulong Jiang¹⁵, Jin Li¹⁶, John M Asara⁹, Myles Brown¹⁷, Mien-Chie Hung¹⁸, Wenyi Wei¹⁹

Affiliations

¹ Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: lixin.wan@moffitt.org.
² Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
³ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁵ Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
⁶ Cell Signaling Technology, Danvers, MA 01923, USA.
⁷ Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
⁸ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Chinese National Human Genome Center at Shanghai, Shanghai 201203, PRC.
⁹ Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹⁰ Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
¹¹ Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
¹² Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, PRC.
¹⁴ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cardiovascular Research Center, Xi'an Jiaotong University School of Medicine, Xi'an 710061, PRC.
¹⁵ Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Oncology, Jining First People's Hospital, Jining, Shandong 272111, PRC; Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, PRC.
¹⁶ Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Urology, 254th Hospital of PLA, Tianjin 300142, PRC.
¹⁷ Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: myles_brown@dfci.harvard.edu.
¹⁸ Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan. Electronic address: mhung@mdanderson.org.
¹⁹ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: wwei2@bidmc.harvard.edu.

Abstract

Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.

Keywords: AMPK; EZH2; metformin; ovarian cancer; phosphorylation; polycomb repressive complex 2.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

AMP-Activated Protein Kinases / metabolism*
Animals
Carcinogenesis / genetics
Cell Cycle
Cell Line, Tumor
Cell Proliferation
DNA Methylation
DNA-Binding Proteins / metabolism
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism*
Enhancer of Zeste Homolog 2 Protein / physiology
Epigenesis, Genetic
Female
Histones / metabolism
Humans
Mice
Neoplasm Proteins
Nuclear Proteins / metabolism
Oncogenes
Ovarian Neoplasms / metabolism
Phosphorylation
Polycomb Repressive Complex 2 / metabolism
Polycomb Repressive Complex 2 / physiology
Transcription Factors
Up-Regulation

Substances

DNA-Binding Proteins
Histones
Neoplasm Proteins
Nuclear Proteins
SUZ12 protein, human
Transcription Factors
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Polycomb Repressive Complex 2
AMP-Activated Protein Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding