CLASS I HISTONE DEACETYLASES REGULATE P53/NF-ΚB CROSSTALK IN CANCER CELLS
Claudia Schäfer, Anja Göder, Mandy Beyer, Nicole Kiweler, Nisintha Mahendrarajah, Anke Raucha, Teodora Nikolova, Natasa Stojanovic, MartinWieczorek, Thomas R. Reichb, Maja T. Tomicic, Michael Linnebacher, Jürgen Sonnemann, Sascha Dietrich, Andreas Sellmer, Siavosh Mahboobi, Thorsten Heinzel, Günter Schneider, Oliver H. Krämer. (09-11-2016).Elsevier Inc., 2016
Research Area C
The transcription factors NF-κB and p53 as well as their crosstalk determine the fate of tumor cells upon therapeutic interventions. Replicative stress and cytokines promote signaling cascades that lead to the co-regulation of p53 and NF-κB. Consequently, nuclear p53/NF-κB signaling complexes activate NF-κB-dependent survival genes. The 18 histone deacetylases (HDACs) are epigenetic modulators that fall into four classes (I-IV). Inhibitors of histone deacetylases (HDACi) become increasingly appreciated as anti-cancer agents. Based on their effects on p53 and NF-κB, we addressed whether clinically relevant HDACi affect the NF-κB/p53 crosstalk. The chemotherapeuticshydroxyurea, etoposide, and fludarabine halt cell cycle progression, induce DNA damage, and lead to DNA fragmentation. These agents co-induce p53 and NF-κB-dependent gene expression in cell lines from breast and colon cancer and in primary chronic lymphatic leukemia (CLL) cells. Using specific HDACi, we find that the class I subgroup of HDACs, but not the class IIb deacetylase HDAC6, are required for the hydroxyurea-induced crosstalk between p53 and NF-κB. HDACi decrease the basal and stress-induced expression of p53 and block NF-κB-regulated gene expression. We further show that class I HDACi induce senescence in pancreatic cancer cells with mutant p53.