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UBE3B, identified as an oncoprotein, exhibits elevated protein levels in breast cancer. However, the impact of PTM on UBE3B remains unexplored. In this study, we show that VHL is a bona fide E3 ligase for UBE3B. Mechanistically, VHL directly binds to UBE3B, facilitating its lysine 48 (K48)-linked polyubiquitination at K286 and K427 in a prolyl hydroxylase (PHD)-independent manner. Consequently, this promotes the proteasomal degradation of UBE3B. The K286\/427R mutation of UBE3B dramatically abolishes the inhibitory effect of VHL on breast tumor growth and lung metastasis. Additionally, the protein levels of UBE3B and VHL exhibit a negative correlation in breast cancer tissues. These findings delineate an important layer of UBE3B regulation by VHL.<\/jats:p>","DOI":"10.1038\/s41419-024-06844-x","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T17:11:53Z","timestamp":1719249113000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["VHL suppresses UBE3B-mediated breast tumor growth and metastasis"],"prefix":"10.1038","volume":"15","author":[{"given":"Shuo","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9021-3031","authenticated-orcid":false,"given":"Xiong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingru","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8317-0018","authenticated-orcid":false,"given":"Xiaoqian","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3131-7804","authenticated-orcid":false,"given":"Jun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6472-7810","authenticated-orcid":false,"given":"Yijie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3516-9546","authenticated-orcid":false,"given":"Yan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,24]]},"reference":[{"key":"6844_CR1","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/jhg.2016.151","volume":"62","author":"A Kariminejad","year":"2017","unstructured":"Kariminejad A, Ajeawung NF, Bozorgmehr B, Dionne-Laporte A, Molidperee S, Najafi K, et al. 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