Publication Date
2-16-2024
Journal
RNA
DOI
10.1261/rna.079931.123
PMID
38191171
PMCID
PMC10870380
PubMedCentral® Posted Date
3-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Histones, Pancreatic Neoplasms, Polyadenylation, RNA, Messenger, CPSF3, JTE-607, alternative polyadenylation, histone processing, chromatin stability
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation of nontransformed immortalized control pancreatic cells. Mechanistically, JTE-607 induces transcriptional readthrough in replication-dependent histones, reduces core histone expression, destabilizes chromatin structure, and arrests cells in the S-phase of the cell cycle. Therefore, CPSF3 represents a potential therapeutic target for the treatment of PDAC.
Included in
Diseases Commons, Gastroenterology Commons, Neurology Commons, Neurosciences Commons, Oncology Commons, Pediatrics Commons
