Class 1 histone deacetylases and ataxia‐telangiectasia mutated kinase control the survival of murine pancreatic cancer cells upon dntp depletion

Alexandra Nguyen, Melanie Dzulko, Janine Murr, Yun Yen, Günter Schneider, Oliver H. Krämer

研究成果: 雜誌貢獻文章同行評審

摘要

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 re-ductase (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 clini-cally 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 sys-tems, 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.

原文英語
文章編號2520
期刊Cells
10
發行號10
DOIs
出版狀態已發佈 - 十月 2021

ASJC Scopus subject areas

  • 醫藥 (全部)

指紋

深入研究「Class 1 histone deacetylases and ataxia‐telangiectasia mutated kinase control the survival of murine pancreatic cancer cells upon dntp depletion」主題。共同形成了獨特的指紋。

引用此