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 pro-vide 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 se-nescent phenotype. Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senes-cent 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.

Automated summary

This study identifies USP7 as a regulator of melanoma and shows that its downregulation induces cellular senescence, inhibiting tumor growth and proliferation. Transcriptomic and proteomic analysis reveals the targets and networks affected by USP7 depletion. RRM2 is identified as a target of USP7 and is regulated by USP7 during the S phase of the cell cycle. Combination therapy using a USP7 inhibitor and a histone deacetylase (HDAC)/LSD1 inhibitor eliminates senescent cells.