{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:05:49Z","timestamp":1789707949232,"version":"4.0.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    Pyruvate kinase M2 (PKM2) is a critical rate-limiting enzyme in glycolysis and is frequently upregulated in bladder cancer (BCa), contributing to the Warburg effect and tumor progression. However, the mechanism supporting abnormal PKM2 stabilization via deubiquitination in BCa remains to be characterized. Here, we identified ubiquitin C-terminal hydrolase L3 (UCHL3) as a bona fide deubiquitylase of PKM2 in BCa. UCHL3 stabilized PKM2 in a deubiquitylation activity-dependent manner. UCHL3 depletion significantly decreased PKM2 protein levels, suppressed glycolytic activity, and inhibited BCa cell proliferation, colony formation, migration\n                    <jats:italic>in vitro<\/jats:italic>\n                    , as well as xenograft tumor growth\n                    <jats:italic>in vivo<\/jats:italic>\n                    . UCHL3 knockdown accelerated PKM2 proteasomal degradation, while overexpression of wild-type UCHL3\u2014but not the catalytically inactive C95A mutant\u2014directly interacted with PKM2, removed K48-linked ubiquitin chains, and prolonged its half-life. Clinically, UCHL3 was markedly upregulated in BCa tissues and cell lines compared with normal urothelium, correlated with higher tumor grade, and was associated with poor patient prognosis; its expression also positively correlated with PKM2 levels. In general, our results demonstrated that UCHL3 plays a pivotal role in stabilizing PKM2, which in turn facilitates glycolysis and tumorigenesis in BCa, suggesting that UCHL3 may prove to be a potential target for the treatment of BCa.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1883763","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:30:58Z","timestamp":1789705858000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The deubiquitinating enzyme UCHL3 promotes bladder cancer progression and glycolysis through enhancing PKM2 protein stability"],"prefix":"10.3389","volume":"16","author":[{"given":"Gengsheng","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Clinical and Public Health, Jiangsu College of Nursing","place":["Huaian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Taizhou Second People\u2019s Hospital Affiliated to Yangzhou University","place":["Taizhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Wang","sequence":"additional","affiliation":[{"name":"Endoscopy Center, Jiangsu Province (Suqian) Hospital","place":["Suqian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical and Public Health, Jiangsu College of Nursing","place":["Huaian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province, Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqin","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Clinical and Public Health, Jiangsu College of Nursing","place":["Huaian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruirui","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Department, Jiangsu Province (Suqian) Hospital","place":["Suqian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2025.12.011","article-title":"Bladder cancer incidence and mortality: A global overview and recent trends","volume":"89","author":"Filho","year":"2025","journal-title":"Eur 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