Role of histone deacetylases in pancreas: Implications for pathogenesis and therapy

Figure 1 Histone deacetylases and histopathological correlates in the transition from normal to acute/chronic pancreatitis and pancreatic cancer. The trend to increased expression (based on pharmacological inhibition studies) of HDACs from normal to pancreatic cancer tissue is shown in the lower part of the figure. In pancreatic cancer, up-regulation of HDAC-1,-2,-3,-7,-8 could be demonstrated - see text for details - probably offering approaches for personalized therapies based on specific HDAC inhibition. HDAC: Histone deacetylases; AP: Acute pancreatitis; CP: Chronic pancreatitis.

Figure 2 Histone deacetylases in acute and chronic pancreatitis. HDACs induce key pro-inflammatory mediators in AP and CP leading to destruction of pancreatic tissue with necrosis in case of AP and fibrosis/atrophy in case of CP. Inhibition of HDACs by HDACis was shown to significantly antagonist these effects in vitro and in vivo. HDAC: Histone deacetylases; HDACis: Histone deacetylases inhibitors; NG: Neutrophil granulocyte; IL: Interleukin; TNF: Tumor necrosis factor; PDGF: Platelet-derived growth factor; TGF: Transforming growth factor; SAHA: Suberoylanilide hydroxamic acid; SB: Sodium butyrate; TSA: Trichostatin A.

Figure 3 Histone deacetylase involvements in hypoxia inducible factor-1-mediated response to hypoxia. As suggested by Miyake et al[51], HIF-1α is possibly regulated and stabilized by two subunits of the NuRD complex: HDAC1/MTA1. Stabilized HIF-1α induces neo-angiogenesis by up-regulation of VEGF and, furthermore, contributes to EMT via Twist and subsequent inhibition of E-Cadherin expression (CDH1). Expression of E-Cadherin can be additionally repressed by complexes of either HDAC class I with ZEB1 or HDAC1 and 2 with Snail at the CDH1 promoter[56]. HDAC: Histone deacetylases; HIF1: Hypoxia inducible factor-1; MTA1: Metastasis-associated protein 1; VEGF: Vascular endothelial growth factor; EMT: Epithelial-mesenchymal transition; ZEB1: Zinc finger E-box-binding homeobox 1.

Figure 4 Role of histone deacetylase 6 in protein turnover. HDAC6 facilitates un-/misfolded protein degradation by recruiting ubiquinated proteins to the aggresome or proteasome thus protecting tumor cells from apoptosis - see text for details[58]. HDAC6: Histone deacetylase 6.