Deficiency of parkin suppresses melanoma tumor development and metastasis through inhibition of MFN2 ubiquitination.

Parkin, a critical gene of Parkinson's disease, is involved in the development of numerous cancers. However, the effect of parkin deficiency on melanoma growth and metastasis has not been reported. We showed that the tumor size and number of surface lung metastases, and expression of tumor growth and metastasis marker proteins were significantly lower in parkin-KO mice than those observed in non-transgenic controls. In an in vitro study, we also showed that parkin siRNA inhibited cell growth and migration of B16F10 and SK-Mel-28 cells. Parkin-specific ubiquitination of mitofusin-2 (MFN2) was decreased in tumors and metastasized lung tissues of parkin-KO mice. Moreover, we showed that parkin directly binds and ubiquitinates MFN2. Knockdown of MFN2 decreased the expression of Bax and apoptotic cell death, but increased that of Bcl2 and apoptotic cancer cell death. However, these effects were reversed by knockdown of parkin. Conversely, inhibitory effects on melanoma growth and migration of parkin siRNA were reversed by MFN2 siRNA. These data indicate that melanoma development was inhibited in parkin-KO mice through maintaining of MFN2 level by inhibition of ubiquitinating ability of parkin.