Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-11-28

AUTHORS

Juan Liu, Cen Zhang, Yuhan Zhao, Xuetian Yue, Hao Wu, Shan Huang, James Chen, Kyle Tomsky, Haiyang Xie, Christen A. Khella, Michael L. Gatza, Dajing Xia, Jimin Gao, Eileen White, Bruce G. Haffty, Wenwei Hu, Zhaohui Feng

ABSTRACT

Mutations in E3 ubiquitin ligase Parkin have been linked to familial Parkinson’s disease. Accumulating evidence suggests that Parkin is a tumor suppressor, but the underlying mechanism is poorly understood. Here we show that Parkin is an E3 ubiquitin ligase for hypoxia-inducible factor 1α (HIF-1α). Parkin interacts with HIF-1α and promotes HIF-1α degradation through ubiquitination, which in turn inhibits metastasis of breast cancer cells. Parkin downregulation in breast cancer cells promotes metastasis, which can be inhibited by targeting HIF-1α with RNA interference or the small-molecule inhibitor YC-1. We further identify lysine 477 (K477) of HIF-1α as a major ubiquitination site for Parkin. K477R HIF-1α mutation and specific cancer-associated Parkin mutations largely abolish the functions of Parkin to ubiquitinate HIF-1α and inhibit cancer metastasis. Importantly, Parkin expression is inversely correlated with HIF-1α expression and metastasis in breast cancer. Our results reveal an important mechanism for Parkin in tumor suppression and HIF-1α regulation. More... »

PAGES

1823

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-017-01947-w

    DOI

    http://dx.doi.org/10.1038/s41467-017-01947-w

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1092917895

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29180628


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