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Article

Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion

1
Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, 55131 Mainz, Germany
2
Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, 81675 München, Germany
3
Ph.D. Program for Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu Hsing Street, Taipei 110, Taiwan
4
Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany
*
Author to whom correspondence should be addressed.
Equal last authorship contribution.
Academic Editors: Mojgan Djavaheri-Mergny and Mohammad Amin Moosavi
Cells 2021, 10(10), 2520; https://doi.org/10.3390/cells10102520
Received: 12 July 2021 / Revised: 13 September 2021 / Accepted: 18 September 2021 / Published: 23 September 2021
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a dismal prognosis. Here, we show how an inhibition of de novo dNTP synthesis by the ribonucleotide reductase (RNR) inhibitor hydroxyurea and an inhibition of epigenetic modifiers of the histone deacetylase (HDAC) family affect short-term cultured primary murine PDAC cells. We used clinically relevant doses of hydroxyurea and the class 1 HDAC inhibitor entinostat. We analyzed the cells by flow cytometry and immunoblot. Regarding the induction of apoptosis and DNA replication stress, hydroxyurea and the novel RNR inhibitor COH29 are superior to the topoisomerase-1 inhibitor irinotecan which is used to treat PDAC. Entinostat promotes the induction of DNA replication stress by hydroxyurea. This is associated with an increase in the PP2A subunit PR130/PPP2R3A and a reduction of the ribonucleotide reductase subunit RRM2 and the DNA repair protein RAD51. We further show that class 1 HDAC activity promotes the hydroxyurea-induced activation of the checkpoint kinase ataxia-telangiectasia mutated (ATM). Unlike in other cell systems, ATM is pro-apoptotic in hydroxyurea-treated murine PDAC cells. These data reveal novel insights into a cytotoxic, ATM-regulated, and HDAC-dependent replication stress program in PDAC cells. View Full-Text
Keywords: apoptosis; ATM; cancer; DNA damage; HDAC; PDAC cells; replication stress; RNR apoptosis; ATM; cancer; DNA damage; HDAC; PDAC cells; replication stress; RNR
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MDPI and ACS Style

Nguyen, A.; Dzulko, M.; Murr, J.; Yen, Y.; Schneider, G.; Krämer, O.H. Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion. Cells 2021, 10, 2520. https://doi.org/10.3390/cells10102520

AMA Style

Nguyen A, Dzulko M, Murr J, Yen Y, Schneider G, Krämer OH. Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion. Cells. 2021; 10(10):2520. https://doi.org/10.3390/cells10102520

Chicago/Turabian Style

Nguyen, Alexandra, Melanie Dzulko, Janine Murr, Yun Yen, Günter Schneider, and Oliver H. Krämer. 2021. "Class 1 Histone Deacetylases and Ataxia-Telangiectasia Mutated Kinase Control the Survival of Murine Pancreatic Cancer Cells upon dNTP Depletion" Cells 10, no. 10: 2520. https://doi.org/10.3390/cells10102520

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