2. Academic Validation
  3. Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis

Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis

  • Signal Transduct Target Ther. 2023 Mar 6;8(1):95. doi: 10.1038/s41392-022-01302-6.
Ying Dong 1 2,  Hao Hu 1,  Xuan Zhang 1 2,  Yunkai Zhang 1 2,  Xin Sun 1 3,  Hanlin Wang 1 4,  Weijuan Kan 1,  Min-Jia Tan 1 2,  Hong Shi 5,  Yi Zang 6 7 8,  Jia Li 9 10 11 12 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Pharmacy, Henan University, Kaifeng, 475004, China.
  • 4 Department of Pharmacology, Fudan University, Shanghai, 201203, China.
  • 5 Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China. ada-shi@139.com.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. yzang@lglab.ac.cn.
  • 7 Lingang laboratory, Shanghai, 201203, China. yzang@lglab.ac.cn.
  • 8 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. yzang@lglab.ac.cn.
  • 9 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jli@simm.ac.cn.
  • 10 University of Chinese Academy of Sciences, Beijing, 100049, China. jli@simm.ac.cn.
  • 11 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. jli@simm.ac.cn.
  • 12 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. jli@simm.ac.cn.
  • 13 Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China. jli@simm.ac.cn.
PMID: 36872368 DOI: 10.1038/s41392-022-01302-6
Abstract

Epithelial to mesenchymal transition (EMT) plays a crucial role in Cancer metastasis, accompanied with vast epigenetic changes. AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although a few studies have shed LIGHT on AMPK regulating Cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein we show that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1) during EMT processes and inhibits lung Cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2. Genetic deletion of PHF2 aggravates lung Cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effect of metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering the transcription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reduces H3K9me2 and suppresses lung Cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the anti-metastasis effect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung Cancer patients and the higher phosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung Cancer metastasis via PHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as the potential epigenetic target in Cancer metastasis.

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