Deubiquitylase PSMD14 inhibits autophagy to promote ovarian cancer progression via stabilization of LRPPRC

Autophagy is a key cellular process, which exists in many tumors and plays dual roles in tumor promotion and suppression. However, the role and mechanism of aberrant autophagy in ovarian cancer remains unclear. Ubiquitin-proteasome pathway is the most important pathway for specific protein degradation. Deubiquitinases (DUBs) have crucial roles in all the stages of tumorigenesis and progression. Herein, we explore the DUBs which contribute to aberrant autophagy in ovarian cancer. TCGA data analysis shows that the autophagy level is suppressed, and the selective autophagy receptor SQSTM1/p62 is abnormally high expressed in ovarian cancer. We screen and identify that the deubiquitinase PSMD14 negatively regulates autophagy level. Functional studies show that increased PSMD14 expression remarkably enhances ovarian cancer cells malignancy, whereas knockdown of PSMD14 has the opposite effect. Furthermore, in vivo assays show that knockdown of PSMD14 inhibits the growth, lung and abdominal metastasis of ovarian cancer. Mechanistically, PSMD14 directly interacts with LRPPRC and inhibits its ubiquitination, thereby inhibiting autophagy through LRPPRC/Beclin1-Bcl-2/SQSTM1 signaling pathway. Next, we demonstrate that PSMD14 is upregulated in ovarian cancer and high expression of PSMD14 positively correlates with LRPPRC. Taken together, we clarify the role of autophagy in regulating the ovarian cancer phenotype and provide insights into regulatory mechanism of autophagy in ovarian cancer.