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Glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1) is a member of the \u03b3-glutamylcyclotransferase family and an unfolded protein response pathway regulatory gene. Its biological function and molecular regulatory mechanism, especially regarding energy metabolism underlying LUAD, remain unclear. By utilizing tissue microarray and data from The Cancer Genome Atlas and Gene Expression Omnibus, we found that CHAC1 expression was markedly higher in LUAD tissues than in non-tumor tissues, and was positively correlated with poor prognosis. Phenotypically, CHAC1 overexpression enhanced the proliferation, migration, invasion, tumor sphere formation, and glycolysis ability of LUAD cells, resulting in tumor growth both in vitro and in vivo. Mechanistically, through a shotgun mass spectrometry-based proteomic approach and high-throughput RNA sequencing, we found that CHAC1 acted as a bridge connecting UBA2 and PKM2, enhancing the SUMOylation of PKM2. The SUMOylated PKM2 then transferred from the cytoplasm to the nucleus, activating the expression of glycolysis-related genes and enhancing the Warburg effect. Lastly, E2F Transcription Factor 1 potently activated CHAC1 transcription by directly binding to the CHAC1 promoter in LUAD cells. The results of this study implied that CHAC1 regulates energy metabolism and promotes glycolysis in LUAD progression.<\/jats:p>","DOI":"10.1038\/s41419-024-07114-6","type":"journal-article","created":{"date-parts":[[2024,10,5]],"date-time":"2024-10-05T10:01:33Z","timestamp":1728122493000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["CHAC1 blockade suppresses progression of lung adenocarcinoma by interfering with glucose metabolism via hijacking PKM2 nuclear translocation"],"prefix":"10.1038","volume":"15","author":[{"given":"Junfan","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sixuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0156-046X","authenticated-orcid":false,"given":"Qiwei","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0355-9892","authenticated-orcid":false,"given":"Jinyuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3686-9958","authenticated-orcid":false,"given":"Jiancheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4189-9692","authenticated-orcid":false,"given":"Yiquan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,5]]},"reference":[{"key":"7114_CR1","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nature25183","volume":"553","author":"RS Herbst","year":"2018","unstructured":"Herbst RS, Morgensztern D, Boshoff C. 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This was an inadvertent copy-paste error that occurred during the image assembly process facilitated by Adobe Illustrator software, for which we take full responsibility. We have promptly revised Figure 8D to reflect the correct data. The incorrect use of the image does not affect our conclusion.","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2024","order":8,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":9,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":10,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41419-024-07235-y","URL":"https:\/\/doi.org\/10.1038\/s41419-024-07235-y","order":11,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the Ethical Review Committee of Fujian Cancer Hospital (K2023-139-01) and the Animal Ethics Committee of Fujian Medical University (No. IACUC FJMU 2023-0109), following the Declaration of Helsinki. Informed consent was secured from all participants, and all animal experiments were performed in compliance with the committee\u2019s guidelines and approval.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"728"}}