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.

Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors / L. Granieri, F. Marocchi, M. Melixetian, N. Mohammadi, P. Nicoli, A. Cuomo, T. Bonaldi, S. Confalonieri, F. Pisati, G. Giardina, G. Bertalot, D. Bossi, L. Lanfrancone. - In: CELL REPORTS. - ISSN 2211-1247. - 40:12(2022 Sep 20), pp. 111396.1-111396.29. [10.1016/j.celrep.2022.111396]

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

F. Marocchi;T. Bonaldi
Formal Analysis
;
F. Pisati;
2022

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 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.
CP: Cancer; DUBs; PDX; cellular senescence; combination therapy; metastatic melanoma
Settore BIO/13 - Biologia Applicata
Settore MED/06 - Oncologia Medica
Settore BIO/11 - Biologia Molecolare
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/948849
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