USP22-mediated deubiquitination of PTEN inhibits pancreatic cancer progression by inducing p21 expression.

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a dual lipid and protein phosphatase. Multiple mechanisms contributing to the regulation of PTEN levels have been identified thus far, including post-translational modifications, epigenetic mechanisms, and transcriptional mechanisms. In the present study, we identified ubiquitin-specific peptidase 22 (USP22) as a novel deubiquitination-modifying enzyme of PTEN. Furthermore, by inducing deubiquitination and inhibiting the degradation of PTEN, USP22 could induce cyclin-dependent kinase inhibitor 1A (CDKN1A, also symboled as p21) expression in pancreatic cancer. Besides, MDM2 proto-oncogene (MDM2) inhibitor enhanced the antipancreatic cancer effects of USP22 overexpression. In addition to its regulation of MDM2-tumor protein p53 (p53) signaling, we found that PTEN could induce p21 expression by interacting with ankyrin repeat and KH domain containing 1 (ANKHD1) and inhibiting ANKHD1 binding to the p21 promoter. Taken together, our results indicate that ANKHD1 and MDM2 might be novel therapeutic targets in pancreatic cancer.