Epigenetic modifiers 5-aza-2'-deoxycytidine and valproic acid differentially change viability, DNA damage and gene expression in metastatic and non-metastatic colon cancer cell lines.

Abstract

DNA methylation and histone modifications are major components of cellular epigenetic pattern determining gene expression. Cancer cells have their own epigenetic array, which can be different in cells of primary and metastatic tumors. In the present work we investigated effects of 1 mM valproic acid (VPA), a histone deacetylase inhibitor and 0.2 μM 5-aza-2'-deoxycytidine (5-aza-dC), a DNA demethylation agent, singly or in combination in two colorectal cancer cell lines Caco-2 (non-metastatic) and LoVo (metastatic). Cell viability, DNA damage and the mRNA expression of the CDC25C (cell division cycle 25C), CDKN1A (cyclin dependent kinase inhibitor 1A) and CHEK1 (checkpoint kinase 1), SQSTM1 (sequestosome 1) and ULK1 (unc-51 like autophagy activating kinase 1), RELA (RELA proto-oncogene, NF-κB subunit) and TP53BP1 (tumor protein p53 binding protein 1) genes important in cell cycle regulation, autophagy and cancer progression were investigated. Both drugs induced a moderate decrease in cell viability and significant DNA damage in both cell lines. LoVo cells were more sensitive to VPA and combined treatment than Caco-2. LoVo cells also showed higher expression of genes that are often associated with more aggressive tumors than Caco-2 cells and treatment with the modifiers increased this difference. In conclusion, 5-aza-dC and VPA can induce different effects in metastatic and non-metastatic cancer cell lines and this may be important in determination of epigenetic profile responsible for metastatic properties of cancer cells.