Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis
Abstract Phosphoglycerate mutase 2 (PGAM2) is a crucial glycolytic enzyme. Recently, we have found that both the protein and acetylation levels of PGAM2 are down-regulated in hepatocellular carcinoma (HCC) tissues. However, the functional significance of PGAM2 in HCC progression remains poorly chara...
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Nature Portfolio
2025-05-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-00930-9 |
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| author | Zexuan Wang Yaoyu Guo Kefei Hu Tingjiang He Tong Qin Ludan Zhang Fang Xu Yuanzhi Xu Mingjiao Cheng Jintao Zhang Qianwei Zhao |
| author_facet | Zexuan Wang Yaoyu Guo Kefei Hu Tingjiang He Tong Qin Ludan Zhang Fang Xu Yuanzhi Xu Mingjiao Cheng Jintao Zhang Qianwei Zhao |
| author_sort | Zexuan Wang |
| collection | DOAJ |
| description | Abstract Phosphoglycerate mutase 2 (PGAM2) is a crucial glycolytic enzyme. Recently, we have found that both the protein and acetylation levels of PGAM2 are down-regulated in hepatocellular carcinoma (HCC) tissues. However, the functional significance of PGAM2 in HCC progression remains poorly characterized. In this study, we demonstrated that PGAM2 functioned as a tumor suppressor in HCC progression, and knockdown of PGAM2 promoted proliferation of HCC cells and tumor growth both in vitro and in vivo. Moreover, we identified lysine 100 (K100) in PGAM2 as the predominant deacetylation site of sirtuin-2 (SIRT2), and that deacetylation of K100 destabilized PGAM2 by promoting its ubiquitination and degradation. Importantly, we discovered that PGAM2 suppressed aerobic glycolysis through an enzymatic activity-independent mechanism in HCC cells. Mechanistic investigations revealed that PGAM2 knockdown upregulated lactate dehydrogenase A (LDHA) expression via activation of the signal transducer and activator of transcription 3 (STAT3). Furthermore, we found that knockdown of PGAM2 sensitized HCC cells to sorafenib treatment. In conclusion, these findings elucidate the tumor-suppressive role of PGAM2 in HCC progression and its post-translational regulation through SIRT2-mediated deacetylation, which provide novel biomarkers and therapeutic targets for HCC treatment. |
| format | Article |
| id | doaj-art-1b07af2a7b3f4f3aa98650ca7c92cc9a |
| institution | OA Journals |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-1b07af2a7b3f4f3aa98650ca7c92cc9a2025-08-20T01:51:59ZengNature Portfolionpj Precision Oncology2397-768X2025-05-019111310.1038/s41698-025-00930-9Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysisZexuan Wang0Yaoyu Guo1Kefei Hu2Tingjiang He3Tong Qin4Ludan Zhang5Fang Xu6Yuanzhi Xu7Mingjiao Cheng8Jintao Zhang9Qianwei Zhao10Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversitySchool of Bioengineering, Sichuan University of Science & EngineeringHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityThe First Affiliated Hospital of Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityAbstract Phosphoglycerate mutase 2 (PGAM2) is a crucial glycolytic enzyme. Recently, we have found that both the protein and acetylation levels of PGAM2 are down-regulated in hepatocellular carcinoma (HCC) tissues. However, the functional significance of PGAM2 in HCC progression remains poorly characterized. In this study, we demonstrated that PGAM2 functioned as a tumor suppressor in HCC progression, and knockdown of PGAM2 promoted proliferation of HCC cells and tumor growth both in vitro and in vivo. Moreover, we identified lysine 100 (K100) in PGAM2 as the predominant deacetylation site of sirtuin-2 (SIRT2), and that deacetylation of K100 destabilized PGAM2 by promoting its ubiquitination and degradation. Importantly, we discovered that PGAM2 suppressed aerobic glycolysis through an enzymatic activity-independent mechanism in HCC cells. Mechanistic investigations revealed that PGAM2 knockdown upregulated lactate dehydrogenase A (LDHA) expression via activation of the signal transducer and activator of transcription 3 (STAT3). Furthermore, we found that knockdown of PGAM2 sensitized HCC cells to sorafenib treatment. In conclusion, these findings elucidate the tumor-suppressive role of PGAM2 in HCC progression and its post-translational regulation through SIRT2-mediated deacetylation, which provide novel biomarkers and therapeutic targets for HCC treatment.https://doi.org/10.1038/s41698-025-00930-9 |
| spellingShingle | Zexuan Wang Yaoyu Guo Kefei Hu Tingjiang He Tong Qin Ludan Zhang Fang Xu Yuanzhi Xu Mingjiao Cheng Jintao Zhang Qianwei Zhao Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis npj Precision Oncology |
| title | Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis |
| title_full | Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis |
| title_fullStr | Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis |
| title_full_unstemmed | Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis |
| title_short | Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis |
| title_sort | hepatocellular carcinoma cells downregulate pgam2 via sirt2 mediated deacetylation modification to enhance aerobic glycolysis |
| url | https://doi.org/10.1038/s41698-025-00930-9 |
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