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UBE3B promotes breast cancer progression by antagonizing HIF-2α degradation

Oncogene volume 42, pages 3394–3406 (2023)Cite this article

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Abstract

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.

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Fig. 1: UBE3B promotes the tumorigenic potential of breast cancer cells.
Fig. 2: UBE3B is required for breast tumor growth and metastasis.
Fig. 3: UBE3B interacts with HIF-2α in vitro and in vivo.
Fig. 4: UBE3B upregulates HIF-2α protein levels in breast cancer cells.
Fig. 5: UBE3B ubiquitylates HIF-2α at lysine residues 394, 497, and 503.
Fig. 6: UBE3B promotes HIF-2α transcriptional activity.
Fig. 7: UBE3B promotes breast tumor growth and metastasis via HIF-2α.

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Data availability

UBE3B expression data in human breast tumors in the TCGA dataset were downloaded from the UCSC Cancer Browser (http://genome-cancer.ucsc.edu). UBE3B mRNA expression was queried in adjacent normal breast tissues and primary and metastatic breast tumors with different stages or grades. Kaplan–Meier survival analysis was performed in breast cancer patients who were divided by medium expression levels of UBE3B mRNA. Kaplan–Meier plotter (http://kmplot.com) was utilized for overall survival analysis for breast cancer patients who were divided according to UBE3B protein levels. All data generated or analyzed during this study are included in this article and its supplementary information files. Any additional data presented in this paper are available from the corresponding author upon request.

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Acknowledgements

We thank The First Affiliated Hospital of Jinan University (JNU) and JNU Animal Studies Core for excellent help. We are grateful to Tongzheng Liu (Jinan University) for VHL and Cul2 plasmids. This work was supported by grants from the National Natural Science Foundation of China (81902691 and 82203297), Taishan Scholar Young Expert Program of Shandong Province (tsqn202306154 and tsqn202306155), Shandong Excellent Young Scientists Fund Program (Overseas) (2022HWYQ-077), Shandong Provincial Natural Science Foundation (ZR2023MH252), Guangdong Basic and Applied Basic Research Foundation (2022A1515011738 and 2021A1515011224), Guangzhou Science and Technology Program (202102080147).

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  1. These authors contributed equally: Yijie Wang, Xiong Liu.

Authors and Affiliations

  1. Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, Center for Cell Structure and Function, Institute of Biomedical Science, College of Life Sciences, Shandong Normal University, Jinan, Shandong, 250014, China

    Yijie Wang, Min Wang, Yu Wang, Shuo Wang, Min Liu, Jun Zhou & Yan Chen

  2. School of Medicine, Jinan University, Guangzhou, Guangdong, 510632, China

    Xiong Liu & Yan Chen

  3. School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, 211166, China

    Lai Jin

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Contributions

YC supervised the project; YC, Yijie Wang, and XL designed experiments. Yijie Wang, XL, MW, Yu Wang, SW, and LJ performed experiments. Yijie Wang, XL, ML, JZ, and YC analyzed the data. Yijie Wang, XL, ML, JZ, and YC wrote the paper.

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Correspondence to Yan Chen.

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Wang, Y., Liu, X., Wang, M. et al. UBE3B promotes breast cancer progression by antagonizing HIF-2α degradation. Oncogene 42, 3394–3406 (2023). https://doi.org/10.1038/s41388-023-02842-z

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