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World J Gastrointest Oncol. Dec 15, 2015; 7(12): 473-483
Published online Dec 15, 2015. doi: 10.4251/wjgo.v7.i12.473
Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy
Eckhard Klieser, Stefan Swierczynski, Christian Mayr, Johanna Schmidt, Daniel Neureiter, Tobias Kiesslich, Romana Illig
Eckhard Klieser, Johanna Schmidt, Daniel Neureiter, Romana Illig, Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Stefan Swierczynski, Department of Surgery, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Christian Mayr, Tobias Kiesslich, Department of Internal Medicine I, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Christian Mayr, Tobias Kiesslich, Laboratory for Tumour Biology and Experimental Therapies (TREAT), Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
Author contributions: Neureiter D and Illig R outlined the manuscript; Klieser E, Swierczynski S, Mayr C, Neureiter D and Kiesslich T researched the literature and contributed individual chapters of the manuscript; Mayr C and Kiesslich T designed the figures; Schmidt J did proofreading and contributed to textual revision of the manuscript.
Conflict-of-interest statement: The authors declared no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Daniel Neureiter, MA, Associate Professor, Institute of Pathology, Paracelsus Medical University, Salzburger Landeskliniken (SALK), Müllner Haupstrasse 48, 5020 Salzburg, Austria. d.neureiter@salk.at
Telephone: +43-662-44824701
Received: June 19, 2015
Peer-review started: June 21, 2015
First decision: August 14, 2015
Revised: September 3, 2015
Accepted: October 20, 2015
Article in press: October 27, 2015
Published online: December 15, 2015
Processing time: 177 Days and 22 Hours
Abstract

In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis (AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future therapies. Histone deacetylases (HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcription. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors.

Keywords: Pancreatitis; Pancreatic cancer; Epigenetics; Histone deacetylase; Histone deacetylase inhibitor

Core tip: Histone deacetylases (HDACs) are epigenetic regulators that play an essential role in organ development and tissue homeostasis. Aberrant HDAC activity contributes to the development of several diseases, including acute and chronic pancreatitis as well as pancreatic cancer. In acute and chronic pancreatitis the inhibition of HDACs exerts significant positive effects of cytokine- and nuclear factor-κB transmitted inflammation and tissue damage paralleled by reduced oxidative stress. HDACs are expressed in pancreatic cancer and were functionally linked to key processes of tumor progression (epithelial-mesenchymal-transition, the ubiquitin-proteasome pathway and angiogenesis), indicating a pleiotropic effect of HDACs in pancreatic cancerogenesis. Treatment of pancreatic cancer cells in vitro with HDAC inhibitors alone and/or in combination with conventional cancer agents resulted in diverse beneficial effects, including inhibition of proliferation and cell cycle as well as apoptosis. Therefore, inhibition of HDACs might be a promising strategy for treatment of pancreatic cancer.