CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing
Histones
Pancreatic Neoplasms
Gene Expression Regulation, Neoplastic
0303 health sciences
03 medical and health sciences
Cell Line, Tumor
Humans
Articles
RNA, Messenger
Polyadenylation
Cell Proliferation
DOI:
10.1261/rna.079931.123
Publication Date:
2024-01-10T07:25:03Z
AUTHORS (15)
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), 3′ endonuclease that catalyzes mRNA during histone processing. We find CPSF3 highly expressed in PDAC associated poor prognosis. knockdown blocks cell proliferation colony formation vitro tumor growth vivo. Chemical inhibition by small molecule JTE-607 also attenuates formation, while it has no effect on nontransformed immortalized control pancreatic cells. Mechanistically, induces transcriptional readthrough replication-dependent histones, reduces core expression, destabilizes chromatin structure, arrests cells S-phase cycle. Therefore, represents potential therapeutic for PDAC.
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