Format

Send to

Choose Destination
Nat Commun. 2017 Nov 28;8(1):1823. doi: 10.1038/s41467-017-01947-w.

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

Author information

1
Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, New Brunswick, NJ, 08903, USA.
2
Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
3
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
4
School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China.
5
Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, New Brunswick, NJ, 08903, USA. wh221@cinj.rutgers.edu.
6
Department of Pharmacology, Rutgers, State University of New Jersey, Piscataway, NJ, 08854, USA. wh221@cinj.rutgers.edu.
7
Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, New Brunswick, NJ, 08903, USA. fengzh@cinj.rutgers.edu.
8
Department of Pharmacology, Rutgers, State University of New Jersey, Piscataway, NJ, 08854, USA. fengzh@cinj.rutgers.edu.

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.

PMID:
29180628
PMCID:
PMC5703960
DOI:
10.1038/s41467-017-01947-w
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center