Histone acetyltransferases and deacetylases: molecular and clinical implications to gastrointestinal carcinogenesis

Abstract

Histone acetyltransferases and deacetylases are two groups of enzymes whose opposing activities govern the dynamic levels of reversible acetylation on specific lysine residues of histones and many other proteins. Gastrointestinal (GI) carcinogenesis is a major cause of morbidity and mortality worldwide. In addition to genetic and environmental factors, the role of epigenetic abnormalities such as aberrant histone acetylation has been recognized to be pivotal in regulating benign tumorigenesis and eventual malignant transformation. Here we provide an overview of histone acetylation, list the major groups of histone acetyltransferases and deacetylases, and cover in relatively more details the recent studies that suggest the links of these enzymes to GI carcinogenesis. As potential novel therapeutics for GI and other cancers, histone deacetylase inhibitors are also discussed.

Histone acetyltransferase PCAF Up-regulated cell apoptosis in hepatocellular carcinoma via acetylating histone H4 and inactivating AKT signaling

“…This modification leads to relaxation of chromatin structure facilitating transcriptional factors to bind with relevant promoters of target gene sequences and consequently controls numerous cell signal pathways {Shogren-Knaak, 2006 #14} [9]. Through regulating lots of cell pathways which control cell fate simultaneity, histone acetylation has been found to contribute to inhibit the growth and metastasis of gastrointestinal cancers including gastric cancer, colorectal cancer and HCC [10,11]. Yamashita et al found that down-regulating acetylation of histone H4 by histone deacetylase inhibitor trichostatin A (TSA) resulted in cell-cycle arrest and apoptosis of HCC cells (HepG2 cells and Huh7 cells, respectively) [12].…”

Anti-CSC Effects in Human Esophageal Squamous Cell Carcinomas and Eca109/9706 Cells Induced by Nanoliposomal Quercetin Alone or Combined with CD 133 Antiserum

“…The quercetin flavonoids are capable to act as anti-inflammatory agents via modulation of pro-inflammatory gene expression and signal transduction pathways (Tuñón,et al,2009). Activated NF-κBp65 (RelA) and the aberrant HDAC activity play the pivotal role of tumorigenesis (Sun et al, 2012;Seidel et al, 2012). Additionally there is link between RelA/p65 and class I HDACs in nuclear translocation as well as RelA/p65 DNA binding activity (Lehmann, et al, 2009).…”

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

“…Even thought it has been recognized that the major reason for GI carcinogenesis resides in at least one genetic mutation that either activates an oncogene or inhibits the function of a tumor suppressor gene, recent data indicate that epigenetic abnormalities are critical in regulating benign tumorigenesis and eventual malignant transformation in gastorointestinal (GI) carcinogenesis [196-202]. In particular, aberrant histone acetylation regulated by HATs and HDACs have been linked to gastric cancer [196]. Epigenetic alterations have also been identified in presence of Epstein-Barr virus [203-205], while Helicobacter pylori , which constitutes a main cause of gastric cancer, was shown to reduce HDACs activity.…”

“…A Phase I study has combined Vorinostat with radiotherapy in GI carcinoma [208]. This, as well as other studies, created foundations for additional initiatives to improve the therapeutic potential of HDACi and other epigenetic enzymes for GI tumors [196]. …”