HDAC inhibitors show differential epigenetic regulation and cell survival strategies on p53 mutant colon cancer cells

• Published in: Journal of biomolecular structure & dynamics 2018-03, Vol.36 (4), p.938-955
• Main Authors: R., Mahalakshmi, P., Husayn Ahmed, Mahadevan, Vijayalakshmi
• Format: Article
• Language: English
• Subjects: Benzamides - pharmacology; Butyric Acid - pharmacology; Cell Survival - drug effects; clonogenic assays; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Computer Simulation; DNA Methylation - drug effects; DNA Methylation - genetics; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; epigenetic regulation; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; HDAC inhibition; Histone Deacetylase Inhibitors - pharmacology; Humans; methylation; Mutation; p53 mutation; Pyridines - pharmacology; Tumor Suppressor Protein p53 - genetics; Valproic Acid - pharmacology
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2017.1302820

Besides inactivating tumour suppressor activity in cells, mutations in p53 confer significant oncogenic functions and promote metastasis and resistance to anticancer therapy. A variety of therapies involving genetic and epigenetic signalling events regulate tumorogenesis and progression in such cases. Pharmacological interventions with HDAC inhibitors have shown promise in therapy. This work explores the changes in efficacy of the four HDAC inhibitors SAHA, MS-275, valproic acid and sodium butyrate on a panel of colon cancer cell lines - HCT116 (p53 wt), HCT116 p53-/-, HT29 and SW480 (with mutations in p53). Clonogenic assays, gene profiling and epigenetic expression done on these cells point to p53 dependent differential activity of the 4 HDAC inhibitors which also elevate methylation levels in p53 mutant cell lines. In silico modelling establishes the alterations in interactions that lead to such differential activity of valproic acid, one of the inhibitors considered for the work. Molecular Dynamic simulations carried out on the valproic acid complex ensure stability of the complex. This work establishes a p53 dependent epigenetic signalling mechanism triggered by HDAC inhibition expanding the scope of HDAC inhibitors in adjuvant therapy for p53 mutant tumours.