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

2018; Elsevier BV; Volume: 69; Issue: 2 Linguagem: Inglês

10.1016/j.molcel.2017.12.024

1097-4164

Lixin Wan, Kexin Xu, Yongkun Wei, Jinfang Zhang, Tao Han, Christopher J. 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,

Metabolism, Diabetes, and Cancer

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.