{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T06:29:15Z","timestamp":1791872955661,"version":"4.3.4"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T00:00:00Z","timestamp":1719792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2023YFC2507003"],"award-info":[{"award-number":["2023YFC2507003"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82173266,81972385,32322023,82173272,81825016,82173230,82341018,82372685,82203662,82173271,82103416,82103536,82202276"],"award-info":[{"award-number":["82173266,81972385,32322023,82173272,81825016,82173230,82341018,82372685,82203662,82173271,82103416,82103536,82202276"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Guangdong Provincial Clinical Research Center for Urological Diseases","award":["2020B1111170006"],"award-info":[{"award-number":["2020B1111170006"]}]},{"DOI":"10.13039\/501100012245","name":"Science and Technology Planning Project of Guangdong Province","doi-asserted-by":"crossref","award":["2023B1212060013"],"award-info":[{"award-number":["2023B1212060013"]}],"id":[{"id":"10.13039\/501100012245","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Areas Research and Development Program of Guangdong","award":["2022B1515120086,2021B1515020091,2022A1515140175,2021A1515010215,2023A1515011648,2022A1515012288,2021A1515010355"],"award-info":[{"award-number":["2022B1515120086,2021B1515020091,2022A1515140175,2021A1515010215,2023A1515011648,2022A1515012288,2021A1515010355"]}]},{"name":"Science and Technology Program of Guangzhou, China","award":["2023A04J2206"],"award-info":[{"award-number":["2023A04J2206"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,1]]},"abstract":"<jats:p>\n                    Ubiquitination plays an essential role in protein stability, subcellular localization, and interactions. Crosstalk between different types of ubiquitination results in distinct biological outcomes for proteins. However, the role of ubiquitination-related crosstalk in lymph node (LN) metastasis and the key regulatory factors controlling this process have not been determined. Using high-throughput sequencing, we found that ubiquitin-conjugating enzyme E2 C (\n                    <jats:italic>UBE2C<\/jats:italic>\n                    ) was overexpressed in bladder cancer (BCa) and was strongly associated with an unfavorable prognosis. Overexpression of\n                    <jats:italic>UBE2C<\/jats:italic>\n                    increased BCa lymphangiogenesis and promoted LN metastasis both in vitro and in vivo. Mechanistically, UBE2C mediated sodium-coupled neutral amino acid transporter 2 (SNAT2) monoubiquitination at lysine 59 to inhibit K63-linked polyubiquitination at lysine 33 of SNAT2. Crosstalk between monoubiquitination and K63-linked polyubiquitination increased SNAT2 membrane protein levels by suppressing epsin 1\u2013mediated (EPN1-mediated) endocytosis. SNAT2 facilitated glutamine uptake and metabolism to promote VEGFC secretion, ultimately leading to lymphangiogenesis and LN metastasis in patients with BCa. Importantly, inhibition of\n                    <jats:italic>UBE2C<\/jats:italic>\n                    significantly attenuated BCa lymphangiogenesis in a patient-derived xenograft model. Our results reveal the mechanism by which UBE2C mediates crosstalk between the monoubiquitination and K63-linked polyubiquitination of SNAT2 to promote BCa metastasis and identify UBE2C as a promising target for treating LN-metastatic BCa.\n                  <\/jats:p>","DOI":"10.1172\/jci179122","type":"journal-article","created":{"date-parts":[[2024,6,30]],"date-time":"2024-06-30T14:00:35Z","timestamp":1719756035000},"source":"Crossref","is-referenced-by-count":30,"title":["UBE2C-induced crosstalk between mono- and polyubiquitination of SNAT2 promotes lymphatic metastasis in bladder cancer"],"prefix":"10.1172","volume":"134","author":[{"given":"Wenjie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China."},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicinem, Guangdong, 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