1. Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression
- Author
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Juan Liu, Yuhan Zhao, Zhaohui Feng, Xuetian Yue, Cen Zhang, Shan Huang, James C. W. Chen, Michael L. Gatza, Christen A. Khella, Bruce G. Haffty, Hao Wu, Dajing Xia, Kyle Tomsky, Eileen White, Jimin Gao, Haiyang Xie, and Wenwei Hu
- Subjects
0301 basic medicine ,Indazoles ,Lung Neoplasms ,Ubiquitin-Protein Ligases ,Science ,Down-Regulation ,General Physics and Astronomy ,Breast Neoplasms ,Transfection ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Parkin ,Metastasis ,Mice ,03 medical and health sciences ,Ubiquitin ,Downregulation and upregulation ,Cell Movement ,RNA interference ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,lcsh:Science ,Mice, Inbred BALB C ,Mutation ,Multidisciplinary ,biology ,Ubiquitination ,Cancer ,General Chemistry ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,nervous system diseases ,3. Good health ,Ubiquitin ligase ,030104 developmental biology ,MCF-7 Cells ,biology.protein ,Cancer research ,Heterografts ,Female ,lcsh:Q - 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., Parkin is an E3 ubiquitin ligase involved in Parkinson’s disease. Parkin has also been linked to cancer suppression but the mechanisms are unclear. Here the authors show that Parkin regulates HIF-1α through ubiquitin-dependent degradation, thus inhibiting metastasis of breast cancer cells.
- Published
- 2017