Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis
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 A...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-03-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-022-01302-6 |
| _version_ | 1797863417069961216 |
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| author | Ying Dong Hao Hu Xuan Zhang Yunkai Zhang Xin Sun Hanlin Wang Weijuan Kan Min-jia Tan Hong Shi Yi Zang Jia Li |
| author_facet | Ying Dong Hao Hu Xuan Zhang Yunkai Zhang Xin Sun Hanlin Wang Weijuan Kan Min-jia Tan Hong Shi Yi Zang Jia Li |
| author_sort | Ying Dong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T22:35:16Z |
| format | Article |
| id | doaj.art-a488fccc803548f08f462353d2ebe4ac |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-04-09T22:35:16Z |
| publishDate | 2023-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-a488fccc803548f08f462353d2ebe4ac2023-03-22T12:31:12ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-03-018111710.1038/s41392-022-01302-6Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasisYing Dong0Hao Hu1Xuan Zhang2Yunkai Zhang3Xin Sun4Hanlin Wang5Weijuan Kan6Min-jia Tan7Hong Shi8Yi Zang9Jia Li10State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesAbstract 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.https://doi.org/10.1038/s41392-022-01302-6 |
| spellingShingle | Ying Dong Hao Hu Xuan Zhang Yunkai Zhang Xin Sun Hanlin Wang Weijuan Kan Min-jia Tan Hong Shi Yi Zang Jia Li Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis Signal Transduction and Targeted Therapy |
| title | Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis |
| title_full | Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis |
| title_fullStr | Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis |
| title_full_unstemmed | Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis |
| title_short | Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis |
| title_sort | phosphorylation of phf2 by ampk releases the repressive h3k9me2 and inhibits cancer metastasis |
| url | https://doi.org/10.1038/s41392-022-01302-6 |
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