CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing

• DOI: 10.1261/rna.079931.123
• Publication Date: 2024-01-10T07:25:03Z
• Authors: Abdulrahman A. Al...; Aditi H. Chaubey; Venkata S. Jonnakuti; Arwen A. Tisdale; Carla D. Schwarz; Abigail C. Cornwell; Kathryn E. Maraszek; Emily J. Paterson; Minsuh Kim; Swati Venkat; Eduardo Cortes Gomez; Jianmin Wang; Katerina V. Gurova; Hari Krishna Yala...; Michael E. Feigin
• Keywords: 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

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.