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Class I histone deacetylases regulate p53/NF-kappaB crosstalk in cancer cells

: Schäfer, Claudia; Göder, Anja; Beyer, Mandy; Kiweler, Nicole; Mahendrarajah, Nisintha; Rauch, Anke; Nikolova, Teodora; Stojanovic, Natasa; Wieczorek, Martin; Reich, Thomas R.; Tomicic, Maja T.; Linnebacher, Michael; Sonnemann, Jürgen; Dietrich, Sascha; Sellmer, Andreas; Mahboobi, Siavosh; Heinzel, Thorsten; Schneider, Günter; Krämer, Oliver H.


Cellular signalling 29 (2017), pp.218-225
ISSN: 0898-6568
ISSN: 1873-3913
Journal Article
Fraunhofer ITEM ()
HDAC; HDACi; NF-κB; p53; replicative stress; survivin

The transcription factors NF-kappaB 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-kappaB. Consequently, nuclear p53/NF-kappaB signaling complexes activate NF-kappaB-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-kappaB, we addressed whether clinically relevant HDACi affect the NF-kappaB/p53 crosstalk. The chemotherapeutics hydroxyurea, etoposide, and fludarabine halt cell cycle progression, induce DNA damage, and lead to DNA fragmentation. These agents co-induce p53 and NF-kappaB-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-kappaB. HDACi decrease the basal and stress-induced expression of p53 and block NF-kappaB-regulated gene expression. We further show that class I HDACi induce senescence in pancreatic cancer cells with mutant p53.