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

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 () and Zhaohui Feng ()
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Juan Liu: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Cen Zhang: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Yuhan Zhao: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Xuetian Yue: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Hao Wu: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Shan Huang: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
James Chen: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Kyle Tomsky: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Haiyang Xie: Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine
Christen A. Khella: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Michael L. Gatza: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Dajing Xia: Zhejiang University School of Medicine
Jimin Gao: Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University
Eileen White: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Bruce G. Haffty: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Wenwei Hu: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey
Zhaohui Feng: Robert Wood Johnson Medical School, Rutgers, State University of New Jersey

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01947-w

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