Because USP22 could induce p21 expression via PTEN‐MDM2‐p53 signaling, we hypothesized that MDM2 inhibitor treatment enhanced the antipancreatic cancer effect of USP22 overexpression, which had been verified by combined approach of MDM2 inhibitor treatment and USP22 overexpression in vivo and in vitro. Here, CDKN1A is linked to cancer.