@article{cb1ea104ae724142bfa872f45f033d91,
title = "Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function",
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. The metabolic state of the cell can be connected to gene expression and modification of histones through several mechanisms. Wan et al. find that AMPK-mediated phosphorylation of EZH2 at T311 inhibits PRC2 methyltransferase activity to relieve PRC2-dependent epigenetic silencing and subsequently suppresses tumorigenesis.",
keywords = "AMPK, EZH2, metformin, ovarian cancer, phosphorylation, polycomb repressive complex 2",
author = "Lixin Wan and Kexin Xu and Yongkun Wei and Jinfang Zhang and Tao Han and Christopher Fry and Zhao Zhang and Wang, {Yao Vickie} and Liyu Huang and Min Yuan and Weiya Xia and Chang, {Wei Chao} and Huang, {Wen Chien} and Liu, {Chien Liang} and Chang, {Yuan Ching} and Jinsong Liu and Yun Wu and Jin, {Victor X.} and Xiangpeng Dai and Jianfeng Guo and Jia Liu and Shulong Jiang and Jin Li and Asara, {John M.} and Myles Brown and Hung, {Mien Chie} and Wenyi Wei",
note = "Funding Information: We thank Drs. Hiroyuki Inuzuka, Wenjian Gan, Jianping Guo, and Qing Yin for critical reading of the manuscript; William Hahn and Stuart Orkin for providing reagents; and members of the Wei, Hung, Brown, Xu, and Wan labs for useful discussions. W.W. is a Leukemia and Lymphoma Society Scholar and ACS Research Scholar. This work was supported in part by NIH grants (W.W., R01GM089763 , R01GM094777 , and R01CA177910 ; M.-C.H., R01CA211615 ; M.B., P01CA080111 ; L.W., R00CA183914 ; K.X., R00CA178199 ; J.Z., 1K99CA212292 ; V.X.J., R01GM114142 ), Cancer Prevention Research Institute of Texas Award (M.-C.H., RP150245 ; K.X., RR140072 ), National Breast Cancer Foundation (BCRF-17-069 to M.-C.H.), Breast Cancer Research Foundation (M.-C.H.), the University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (M.-C.H.), V Foundation Translational Award ( T2017-010 to K.X.), and Voelcker Fund Young Investigator Award (K.X.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jan,
day = "18",
doi = "10.1016/j.molcel.2017.12.024",
language = "English (US)",
volume = "69",
pages = "279--291.e5",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}