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

Autor:	Granieri L; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Marocchi F; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Melixetian M; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Mohammadi N; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; Experimental Hematology Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy., Nicoli P; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Cuomo A; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Bonaldi T; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Confalonieri S; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Pisati F; Histopathology Unit, Cogentech S.C.a.R.L, Via Adamello, 20139 Milan, Italy., Giardina G; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy., Bertalot G; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; U.O.M. Anatomia ed Istologia Patologica, Ospedale S. Chiara di Trento, Largo Medaglie d'Oro, 38122 Trento, Italy., Bossi D; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Lanfrancone L; Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy. Electronic address: luisa.lanfrancone@ieo.it.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2022 Sep 20; Vol. 40 (12), pp. 111396.
DOI:	10.1016/j.celrep.2022.111396
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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