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 m...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 afew studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein weshow 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 effectof metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering thetranscription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reducesH3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the antimetastasiseffect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higherphosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis viaPHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as thepotential epigenetic target in cancer metastasis.展开更多
基金China Postdoctoral Science Foundation(Grant 2021M703345)the National Natural Science Foundation of China(Grant 31871414,81821005)+3 种基金Shanghai Science and Technology Development Funds(Grant 22YF1457100,22ZR1415200)the Lingang Laboratory(Grant Nos.LG202103-03-04,LG202103-03-05)Shanghai Special Program for Research on Aging and Women and Children’s Health(No.2020YJZX0136)Talent Program of Shanghai Pulmonary Hospital(No.fkgg1809,fkzr2317).
文摘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 afew studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein weshow 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 effectof metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering thetranscription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reducesH3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the antimetastasiseffect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higherphosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis viaPHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as thepotential epigenetic target in cancer metastasis.
