Impact of Hybrid-polar Histone Deacetylase Inhibitor m-Carboxycinnamic Acid bis-Hydroxyamide on Human Pancreatic Adenocarcinoma Cells.

BACKGROUND: Histone deacetylase inhibitors (HDACIs) have got immense importance as promising drugs for cancer treatment as these inhibitors regulate cellular differentiation, gene expression, cell cycle arrest and apoptosis. The current study investigates the effect of the hybrid-polar HDACI m-carboxycinnamic acid bishydroxyamide (CBHA) on the growth of human pancreatic adenocarcinoma cells, using the cell line MIA PaCa- 2 as an in vitro model. METHODS: Following CBHA treatment of the MIA PaCa-2 cells, we characterized the effect of CBHA by in vitro cytotoxicity evaluation, clonogenic assay, cell cycle analysis, immunoblotting for soluble and insoluble fractions of tubulin, immunofluorescence and caspase-3 assay. RESULTS: We observed that the histone deacetylase inhibitor CBHA markedly impaired growth of the pancreatic cancer cells by resulting in dose-dependent G2/M arrest, disruption of microtubule organization, induction of caspase-mediated apoptosis and in vitro suppression of HDAC6. Our study also shows that inhibition of HDAC6 by CBHA induced acetylation of α-tubulin. CONCLUSION: Together, our findings show that CBHA can be a potential plausible therapeutic that could be exploited for pancreatic cancer therapy.

The role of MOF in the ionizing radiation response is conserved in Drosophila melanogaster.

In Drosophila, males absent on the first (MOF) acetylates histone H4 at lysine 16 (H4K16ac). This acetylation mark is highly enriched on the male X chromosome and is required for dosage compensation in Drosophila but not utilized for such in mammals. Recently, we and others reported that mammalian MOF, through H4K16ac, has a critical role at multiple stages in the DNA damage response (DDR) and double-strand break repair pathways. The goal of this study was to test whether mof is similarly required for the response to ionizing radiation (IR) in Drosophila. We report that Drosophila mof mutations in males and females, as well as mof knockdown in SL-2 cells, reduce post-irradiation survival. MOF depletion in SL-2 cells also results in an elevated frequency of metaphases with chromosomal aberrations, suggesting that MOF is involved in DDR. Mutation in Drosophila mof also results in a defective mitotic checkpoint, enhanced apoptosis, and a defective p53 response post-irradiation. In addition, IR exposure enhanced H4K16ac levels in Drosophila as it also does in mammals. These results are the first to demonstrate a requirement for MOF in the whole animal IR response and suggest that the role of MOF in the response to IR is conserved between Drosophila and mammals.