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

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 1 alpha (HIF-1 alpha). Parkin interacts with HIF-1 alpha and promotes HIF-1 alpha 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-1 alpha with RNA interference or the small-molecule inhibitor YC-1. We further identify lysine 477 (K477) of HIF-1 alpha as a major ubiquitination site for Parkin. K477R HIF-1 alpha mutation and specific cancer-associated Parkin mutations largely abolish the functions of Parkin to ubiquitinate HIF-1 alpha and inhibit cancer metastasis. Importantly, Parkin expression is inversely correlated with HIF-1 alpha expression and metastasis in breast cancer. Our results reveal an important mechanism for Parkin in tumor suppression and HIF-1 alpha regulation.