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

• Published in: Molecular cell Vol. 69; no. 2; pp. 279 - 291.e5
• Main Authors: Wan, Lixin, Xu, Kexin, Wei, Yongkun, Zhang, Jinfang, Han, Tao, Fry, Christopher, Zhang, Zhao, Wang, Yao Vickie, Huang, Liyu, Yuan, Min, Xia, Weiya, Chang, Wei-Chao, Huang, Wen-Chien, Liu, Chien-Liang, Chang, Yuan-Ching, Liu, Jinsong, Wu, Yun, Jin, Victor X., Dai, Xiangpeng, Guo, Jianfeng, Liu, Jia, Jiang, Shulong, Li, Jin, Asara, John M., Brown, Myles, Hung, Mien-Chie, Wei, Wenyi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.01.2018
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; 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; EZH2; Female; Histones - metabolism; Humans; metformin; Mice; Neoplasm Proteins; Nuclear Proteins - metabolism; Oncogenes; ovarian cancer; Ovarian Neoplasms - metabolism; Phosphorylation; polycomb repressive complex 2; Polycomb Repressive Complex 2 - metabolism; Polycomb Repressive Complex 2 - physiology; Transcription Factors; Up-Regulation; AMPK; polycomb repressive complex 2; metformin; ovarian cancer; phosphorylation; EZH2
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2017.12.024

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. [Display omitted] •AMPK activation attenuates PRC2-mediated epigenetic silencing•AMPK phosphorylates EZH2 at T311 to disrupt EZH2-SUZ12 interaction•EZH2 T311 phosphorylation inhibits PRC2 oncogenic function•EZH2 T311 phosphorylation correlates with better survival in cancer patients 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.