{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T03:21:17Z","timestamp":1782962477857,"version":"3.54.5"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T00:00:00Z","timestamp":1652227200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["92057120"],"award-info":[{"award-number":["92057120"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970674"],"award-info":[{"award-number":["81970674"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81902700"],"award-info":[{"award-number":["81902700"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006606","name":"Natural Science Foundation of Tianjin City","doi-asserted-by":"publisher","award":["20JCQNJC00240"],"award-info":[{"award-number":["20JCQNJC00240"]}],"id":[{"id":"10.13039\/501100006606","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019062","name":"Tianjin Research Innovation Project for Postgraduate Students","doi-asserted-by":"publisher","award":["2021YJSB276"],"award-info":[{"award-number":["2021YJSB276"]}],"id":[{"id":"10.13039\/501100019062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019062","name":"Tianjin Research Innovation Project for Postgraduate Students","doi-asserted-by":"publisher","award":["2021YJSS151"],"award-info":[{"award-number":["2021YJSS151"]}],"id":[{"id":"10.13039\/501100019062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Glutaminolysis is a critical metabolic process that promotes cancer cell proliferation, including hepatocellular carcinoma (HCC). Delineating the molecular control of glutaminolysis could identify novel targets to ameliorate this oncogenic metabolic pathway. Here, we evaluated the role of general control of amino acid synthesis 5 like 1 (GCN5L1), a regulator of mitochondrial protein acetylation, in modulating the acetylation and activity of glutaminase to regulate HCC development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cell proliferation was determined by MTT, 2D and soft agar clone formation assays and orthotopic tumour assays in nude mice. GLS1\/2 acetylation and activities were measured in cells and tumours to analyse the correlation with GCN5L1 expression and mTORC1 activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hepatic GCN5L1 ablation in mice markedly increased diethylnitrosamine (DEN)\u2010induced HCC, and conversely, the transduction of mitochondrial\u2010restricted GCN5L1 protected wild\u2010type mice against HCC progression in response to DEN and carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) exposure. GCN5L1\u2013depleted HepG2 hepatocytes enhanced tumour growth in athymic nude mice. Mechanistically, GCN5L1 depletion promoted cell proliferation through mTORC1 activation. Interestingly, liver\u2013enriched glutaminase 2 (GLS2) appears to play a greater role than ubiquitous and canonical tumour\u2013enriched glutaminase 1 (GLS1) in promoting murine HCC. Concurrently, GCN5L1 promotes acetylation and inactivation of both isoforms and increases enzyme oligomerisation. In human HCC tumours compared to adjacent tissue, there were variable levels of mTORC1 activation, GCN5L1 levels and glutaminase activity. Interestingly, the levels of GCN5L1 inversely correlated with mTORC1 activity and glutaminase activity in these tumours.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study identified that glutaminase activity, rather than GLS1 or GLS2 expression, is the key factor in HCC development that activates mTORC1 and promotes HCC. In the Kaplan\u2013Meier analysis of liver cancer, we found that HCC patients with high GCN5L1 expression survived longer than those with low GCN5L1 expression. Collectively, GCN5L1 functions as a tumour regulator by modulating glutaminase acetylation and activity in the development of HCC.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.852","type":"journal-article","created":{"date-parts":[[2022,5,11]],"date-time":"2022-05-11T07:31:08Z","timestamp":1652254268000},"source":"Crossref","is-referenced-by-count":31,"title":["Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Taotao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammatory Biology The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Cui","sequence":"additional","affiliation":[{"name":"Hepatobiliary Surgery Department Tianjin Medical University Cancer Institute and Hospital  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammatory Biology The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammatory Biology The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linmeng","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammatory Biology The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology Tianjin Key Laboratory of Cell Homeostasis and Major Diseases School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammatory Biology The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammatory Biology The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Hepatobiliary Surgery Department Tianjin Medical University Cancer Institute and Hospital  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism NHLBI National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N.","family":"Sack","sequence":"additional","affiliation":[{"name":"Laboratory of Mitochondrial Biology and Metabolism NHLBI National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingdi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology Tianjin Key Laboratory of Cell Homeostasis and Major Diseases School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2716-4649","authenticated-orcid":false,"given":"Lu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Tianjin Key Laboratory of Inflammatory Biology The Province and Ministry Co\u2010sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Sciences Tianjin Medical University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,5,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055\u20109965.EPI\u201020\u20101088"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.05.003"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.11.011"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20100716\u20101476\u20101_11"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.07.003"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.10.002"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010020\u20102475\u20106"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2012748118"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/156800911797264725"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.56749"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.12.015"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2018.11.030"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.08.076"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.10727"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29183"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.07.013"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.08.008"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11457"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.11.016"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30876"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201000521\u20108"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29871"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.02.007"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2021.1894759"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.04.002"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1001006107"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.277483.116"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.01.016"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.10.024"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.02.014"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08778"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201900767R"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.08.020"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30097"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.852","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.852","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.852","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T10:15:19Z","timestamp":1692612919000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.852"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5]]},"references-count":35,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1002\/ctm2.852"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.852","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5]]},"article-number":"e852"}}