Cleavage and polyadenylation machinery as a novel targetable vulnerability for human cancer.

Journal

Cancer gene therapy

ISSN: 1476-5500

Titre abrégé: Cancer Gene Ther

Pays: England

ID NLM: 9432230

Informations de publication

Date de publication:
17 Apr 2024

Historique:

received: 31 01 2024

accepted: 03 04 2024

revised: 28 03 2024

medline: 18 4 2024

pubmed: 18 4 2024

entrez: 17 4 2024

Statut: aheadofprint

Résumé

The role of alternative polyadenylation of mRNA in sustaining aggressive features of tumors is quite well established, as it is responsible for the 3'UTR shortening of oncogenes and subsequent relief from miRNA-mediated repression observed in cancer cells. However, the information regarding the vulnerability of cancer cells to the inhibition of cleavage and polyadenylation (CPA) machinery is very scattered. Only few recent reports show the antitumor activity of pharmacological inhibitors of CPSF3, one among CPA factors. More in general, the fact that deregulated CPA can be seen as a new hallmark of cancer and as a potential reservoir of novel therapeutic targets has never been formalized. Here, to extend our view on the potential of CPA inhibition (CPAi) approaches as anticancer therapies, we systematically tested the fitness of about one thousand cell lines of different cancer types upon depletion of all known CPA factors by interrogating genome-scale CRISPR and RNAi dependency maps of the DepMap project. Our analysis confirmed core and accessory CPA factors as novel vulnerabilities for human cancer, thus highlighting the potential of CPAi as anticancer therapy. Among all, CPSF1 appeared as a promising actionable candidate for drug development, as it showed low dependency scores pancancer and particularly in highly proliferating cells. In a personalized medicine perspective, the observed differential vulnerability of cancer cell lines to selected CPA factors may be used to build up signatures to predict response of individual human tumors to CPAi approaches.

Identifiants

DOI: 10.1038/s41417-024-00770-y PMID: 38632357

pubmed: 38632357

doi: 10.1038/s41417-024-00770-y

pii: 10.1038/s41417-024-00770-y

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)

ID : IG 2020 - ID. 24325

Informations de copyright

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