CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing
- Abdulrahman A. Alahmari1,2,
- Aditi H. Chaubey1,
- Venkata S. Jonnakuti3,4,5,
- Arwen A. Tisdale1,
- Carla D. Schwarz1,
- Abigail C. Cornwell1,
- Kathryn E. Maraszek1,
- Emily J. Paterson1,
- Minsuh Kim1,
- Swati Venkat1,
- Eduardo Cortes Gomez6,
- Jianmin Wang6,
- Katerina V. Gurova7,
- Hari Krishna Yalamanchili3,8,9 and
- Michael E. Feigin1
- 1Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, USA
- 2Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
- 3Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
- 4Program in Quantitative and Computational Biology, Baylor College of Medicine, Houston, Texas 77030, USA
- 5Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA
- 6Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, USA
- 7Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14203, USA
- 8Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA
- 9USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
- Corresponding author: michael.feigin{at}roswellpark.org
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Handling editor: Javier Caceres
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.
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Footnotes
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.079931.123.
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Freely available online through the RNA Open Access option.
- Received December 15, 2023.
- Accepted January 2, 2024.
This article, published in RNA, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
