Targeting histone deacetylases in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a median survival below 6 months and a 5-year survival rate below 1%. Effective therapies for locally advanced or metastatic tumours are missing and curatively resected patients relapse in over 80% of the cases. Although histone deacetylases (HDACs) are involved in the control of proliferation, apoptosis, differentiation, migration and angiogenesis of cancer cells, knowledge about the expression patterns and functions of individual HDAC isoenzymes in pancreatic cancer is sparse. This review summarizes the roles of HDACs as novel therapeutic targets and the molecular mode of action of HDAC-inhibitors (HDACI) in PDACs. Success of HDACI in clinical settings will depend on an increased knowledge of HDAC functions as well as on a better understanding of the mode of action of HDACI. Pre-clinical experimental data that constitute the basis for rational therapeutic strategies to treat PDAC are described here. Translating these rational-based therapies into the clinic will finally increase our chance to establish an effective HDACI-containing combination therapy effective against PDAC.

Fig 1

The HDAC family. HDACs can be classified according to their homology in the catalytic domain into class I (HDAC1, 2, 3 and 8), class II (HDAC4, 5, 6, 7, 9 and 10) and class IV (HDAC11) enzymes. Class II is subdivided depending onto the presence of one (class IIa) or two (class IIb) catalytic domains. The NAD^±-dependent sirtuin protein deacetylases, SIRT1–7, represent class III. aa: amino acids.

Fig 2

HDAC functions and responses in cancer cells. In addition to the deacetylation of histones, HDACs can deacetylate various other proteins. These proteins are often transcription factors. Therefore, HDACs can regulate gene expression by the modulation of chromatin condensation (histone code) and the regulation of transcription factor activity. HDAC-dependent changes in the transcriptome mediate several biological HDAC effects, which are described in the figure.

Fig 3

Characterized pathways engaged by HDACs in PDAC. Three molecular well characterized HDAC controlled processes in PDAC are illustrated. Left part: A HDAC1, 2 containing repressor complex is recruited to the E-box of the E-cadherin promoter by the transcription factor SNAIL, contributing to EMT and metastasis. Middle part: HDACs contribute to the imbalanced expression of anti-apoptotic (BCL_XL, BCLw, MCL1, c-Flip) and pro-apoptotic (BIM, BAX, NOXA) genes, contributing to apop totic and therapeutic resistance of PDAC cells. Right part: HDACs control expression of the CDKI p21^Cip1/Waf1 and cyclin B1 to control G2/M-phase or the CDKI p27^Kip1 to control G1/S-phase of the cell cycle.