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.

Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors / Granieri, L; Marocchi, F; Melixetian, M; Mohammadi, N; Nicoli, P; Cuomo, A; Bonaldi, T; Confalonieri, S; Pisati, F; Giardina, G; Bertalot, G; Bossi, D; Lanfrancone, L. - In: CELL REPORTS. - ISSN 2211-1247. - STAMPA. - 40:12(2022), pp. 11139601-11139618. [10.1016/j.celrep.2022.111396]

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

Bertalot G;
2022-01-01

Abstract

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.
2022
12
Granieri, L; Marocchi, F; Melixetian, M; Mohammadi, N; Nicoli, P; Cuomo, A; Bonaldi, T; Confalonieri, S; Pisati, F; Giardina, G; Bertalot, G; Bossi, D...espandi
Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors / Granieri, L; Marocchi, F; Melixetian, M; Mohammadi, N; Nicoli, P; Cuomo, A; Bonaldi, T; Confalonieri, S; Pisati, F; Giardina, G; Bertalot, G; Bossi, D; Lanfrancone, L. - In: CELL REPORTS. - ISSN 2211-1247. - STAMPA. - 40:12(2022), pp. 11139601-11139618. [10.1016/j.celrep.2022.111396]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/360402
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