E3 泛素连接酶 UBE3B 突变与考夫曼眼脑面部综合征 (KOS) 有关。越来越多的证据表明UBE3B可能在癌症中发挥重要作用。然而，UBE3B 在癌症中的确切作用及其潜在机制在很大程度上仍然未知。在这里，我们报道了 UBE3B 是缺氧诱导因子 2α (HIF-2α) 的 E3 连接酶。从机械角度来看，UBE3B 与 HIF-2α 发生物理相互作用，促进其赖氨酸 63 (K63) 连接的多聚泛素化，从而抑制 Von Hippel-Lindau (VHL) E3 连接酶复合物介导的 HIF-2α 降解。 UBE3B 缺失可在体外抑制乳腺癌细胞增殖、集落形成、迁移和侵袭，并在体内抑制乳腺肿瘤生长和肺转移。我们进一步确定 HIF-2α 的 K394、K497 和 K503 是 UBE3B 的关键泛素化位点。 HIF-2α 的 K394/497/503R 突变可显着消除 UBE3B 介导的乳腺癌生长和肺转移。有趣的是，乳腺癌组织中UBE3B的蛋白水平上调并与HIF-2α蛋白水平呈正相关。这些发现揭示了 UBE3B 在 HIF-2α 调节和乳腺癌进展中发挥作用的关键机制。© 2023。作者，获得 Springer Nature Limited 的独家许可。

Mutations in E3 ubiquitin ligase UBE3B have been linked to Kaufman Oculocerebrofacial Syndrome (KOS). Accumulating evidence indicates that UBE3B may play an important role in cancer. However, the precise role of UBE3B in cancer and the underlying mechanism remain largely uncharted. Here, we reported that UBE3B is an E3 ligase for hypoxia-inducible factor 2α (HIF-2α). Mechanically, UBE3B physically interacts with HIF-2α and promotes its lysine 63 (K63)-linked polyubiquitination, thereby inhibiting the Von Hippel-Lindau (VHL) E3 ligase complex-mediated HIF-2α degradation. UBE3B depletion inhibits breast cancer cell proliferation, colony formation, migration, and invasion in vitro and suppresses breast tumor growth and lung metastasis in vivo. We further identified K394, K497, and K503 of HIF-2α as key ubiquitination sites for UBE3B. K394/497/503R mutation of HIF-2α dramatically abolishes UBE3B-mediated breast cancer growth and lung metastasis. Intriguingly, the protein levels of UBE3B are upregulated and positively correlated with HIF-2α protein levels in breast cancer tissues. These findings uncover a critical mechanism underlying the role of UBE3B in HIF-2α regulation and breast cancer progression.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.