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Corno C, Costantino M, Pettinari P, Mirra L, Stucchi S, Arrighetti N, Perta N, Di Muccio G, Robin M, Beretta GL, Corna E, Carenini N, Cleris L, Colombo D, Luison E, Ciniselli CM, Lecchi M, Verderio P, Figini M, Linder S, Tosi D, La Teana A, D'Arcy P, Perego P
Int. J. Biol. Sci. 22 (11) 5780-5798 [2026-05-29; online 2026-05-29]
Deubiquitinases (DUBs) are proteases with emerging roles in cancer, yet their contribution to drug resistance in ovarian cancer remains underexplored. Ovarian cancer patients often fail to benefit from platinum-based therapy, highlighting the need to identify novel factors driving drug resistance. Thus, we performed a CRISPR/Cas9 screen targeting the DUB family to identify genes essential for cisplatin-resistant ovarian carcinoma cell survival. CRISPR/Cas9 DUB knockout screens, preclinical pharmacology approaches, RNA sequencing, proteomic analyses, computational tools, surface plasma resonance were applied. We identified USP18 as a survival factor in cisplatin-resistant ovarian cancer cells. USP18 expression was elevated at the mRNA and protein levels across five cisplatin-resistant variants. Knockdown and CRISPR/Cas9 editing of USP18 sensitized cells to cisplatin, coinciding with impaired repair of cisplatin-induced DNA damage. Enhanced sensitivity to cisplatin was evident from studies in mice. RNA-seq of USP18 RNA interfered and edited cells revealed the modulation of pathways including DNA repair. A peptide-based USP18 inhibitor suppressed growth of cisplatin-resistant cells, supporting USP18 role in sustaining their growth. We identified USP18 as a novel mediator of cisplatin resistance in ovarian cancer, acting through DNA repair modulation. Targeting USP18 may offer a therapeutic strategy to improve outcomes in platinum-resistant ovarian cancer.
CRISPR Functional Genomics [Service]
PubMed 42328450
DOI 10.7150/ijbs.130399
Crossref 10.7150/ijbs.130399
pmc: PMC13282739
pii: ijbsv22p5780