Details

Autor(en) / Beteiligte

• Alahmari, Abdulrahman A
• Chaubey, Aditi H
• Jonnakuti, Venkata S
• Tisdale, Arwen A
• Schwarz, Carla D
• Cornwell, Abigail C
• Maraszek, Kathryn E
• Paterson, Emily J
• Kim, Minsuh
• Venkat, Swati
• Gomez, Eduardo Cortes
• Wang, Jianmin
• Gurova, Katerina V
• Yalamanchili, Hari Krishna
• Feigin, Michael E

Titel

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

Ist Teil von

• RNA (Cambridge), 2024-03, Vol.30 (3), p.281

Ort / Verlag

United States

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 is highly expressed in PDAC and is associated with poor prognosis. 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.