%0 Journal Article
%T HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells
%A Susanne Sch¨¹ler
%A Petra Fritsche
%A Sandra Diersch
%A Alexander Arlt
%A Roland M Schmid
%A Dieter Saur
%A G¨¹nter Schneider
%J Molecular Cancer
%D 2010
%I BioMed Central
%R 10.1186/1476-4598-9-80
%X Depletion of HDAC2, but not HDAC1, in the pancreatic cancer cell lines MiaPaCa2 and Panc1 resulted in a marked sensitization towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Correspondingly, the more class I selective HDAC inhibitor (HDACI) valproic acid (VPA) synergized with TRAIL to induce apoptosis of MiaPaCa2 and Panc1 cells. At the molecular level, an increased expression of the TRAIL receptor 1 (DR5), accelerated processing of caspase 8, pronounced cleavage of the BH3-only protein Bid, and increased effector caspase activation was observed in HDAC2-depleted and TRAIL-treated MiaPaCa2 cells.Our data characterize a novel HDAC2 function in PDAC cells and point to a strategy to overcome TRAIL resistance of PDAC cells, a prerequisite to succeed with a TRAIL targeted therapy in clinical settings.The incidence of pancreatic ductal adenocarcinoma (PDAC) is only about 10 in 105, but it is the fourth leading cause of cancer-related death with a 5-year survival rate beyond 5% [1]. As there is no significant improvement in patient survival over the last decades [2] and biologicals like the epidermal growth factor receptor (EGFR) inhibitor erlotinib are only active in a subset of patients [3], there is a need to develop new rational based therapeutic strategies in preclinical settings.Histone deacetylases (HDACs) deacetylate the ¦Å-amino group of lysines located at the N-terminal tail of histones, which leads to a repressive chromatin formation (heterochromatin) and the suppression of gene expression [4]. In addition to the condensation of chromatin, HDACs deacetylate various proteins to regulate their function. Many of these proteins are transcription factors, such as p53, C/EBP¦Â, NF-¦ÊB and STATs. Therefore changes in the transcriptome upon HDAC inhibitor (HDACI) treatment can be due to a direct modulation of the "histone code" or the consequence of a rather indirect modulation of signaling pathways and transcription factor activities [5-7]. The
%U http://www.molecular-cancer.com/content/9/1/80