Abstract
BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions.ResultsDepletion 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.ConclusionsOur 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies
In this study we show that specific depletion of HDAC2, but not HDAC1, sensitizes PDAC cells towards tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, suggesting a new therapeutic strategy
The TRAILinduced apoptotic fraction was significantly increased in a dose-dependent manner in HDAC2-depleted MiaPaCa2 and Panc1 cells
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. 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]. Histone deacetylases (HDACs) deacetylate the ε-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/EBPβ, NF-κB and STATs. changes in the transcriptome upon HDAC inhibitor (HDACI) treat-
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