biostudies-literatureYi JU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHS1941https://www.ebi.ac.uk/biostudies/studies/S-EPMC10079682biostudies-literatureUnknown14(1)Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. MoreNature communicationsTargeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy.PMC10079682R35CA253059R01 CA258390R01 CA254970R01 CA227450CA227450RO1CA258390RO1CA254970R35 CA253059P30 CA013696Yi JLi HWang DGu WBaer RJTavana OfalseTargeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy.Since Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. More2023-01-01T00:00:00Z2023 Apr2026-04-30T13:04:53.291Z2024-11-21T02:02:18.611ZS-EPMC100796823702450410.1038/s41467-023-37617-3