Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors

Deubiquitinating enzymes are key regulators of the ubiquitin-proteasome system and cell cycle, and their dysfunction leads to tumorigenesis. Our in vivo drop-out screens in patient-derived xenograft models identify USP7 as a regulator of melanoma. We show that USP7 downregulation induces cellular senescence, arresting melanoma growth in vivo and proliferation in vitro in BRAF- and NRAS-mutant melanoma. We provide a comprehensive understanding of targets and networks affected by USP7 depletion by performing a global transcriptomic and proteomics analysis. We show that RRM2 is a USP7 target and is regulated by USP7 during S phase of the cell cycle. Ectopic expression of RRM2 in USP7-depleted cells rescues the senescent phenotype. Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma. [Display omitted] •Genetic and pharmacological inhibition of USP7 induces senescence in melanoma PDXs•USP7 stabilizes RRM2 by deubiquitination, protecting it from proteasome degradation•Ectopic expression of RRM2 rescues shUSP7-induced senescent phenotype•The HDAC/LSD1 inhibitor domatinostat clears senescent cells induced by USP7 inhibition Granieri et al. describe the prognostic role of USP7 in melanoma and provide evidence of the direct functional interaction of USP7 and RRM2. The USP7/RRM2 axis regulates cell cycle progression and, in turn, senescence. The work proposes a combination therapy for individuals with melanoma by combining USP7 and HDAC/LSD1 inhibitors.