Resveratrol modulates epigenetic regulators of promoter histone methylation and acetylation that restores BRCA1, p53, p21 < sup > CIP1 < /sup > in human breast cancer cell lines

Abstract

The epigenetic enzymes catalyze posttranslational modifications (PTMs) of histones, which functionally determine gene expression at the chromatin level. Resveratrol (RVT) a much studied anti-cancer natural molecule is known for restoration of BRCA1, p53, and p21 in cancer cells. We aimed to investigate the role of histone methylation and acetylation on upregulation of these tumor suppressor genes. Our results suggest RVT significantly increase expression of BRCA1, p53, and p21, while decreased expression of protein arginine methyltransferase 5 (PRMT5) and enhancer of Zeste homolog 2 (EZH2) at a 20 μM concentration by 48 hr in both MCF-7 and MDA-MB-231 breast cancer cells. Also, there was an overall loss of H4R3me2s (catalytic product of PRMT5) and H3K27me3 (catalytic product of PRMT5). In contrast, RVT exposure caused a significant decrease in lysine deacetylase (KDAC) activity and expression of KDAC1-3, whereas the expression of lysine acetyltransferase KAT2A/3B was increased compared to the unexposed cells. As an outcome, RVT increased global level of H3K9ac and H3K27ac marks. The chromatin immunoprecipitation showed 20 μM RVT exposure significantly reduced the enrichment of repressive histone marks (H4R3me2s and H3K27me3) while the abundance of activating histone marks (H3K9/27ac) within the proximal promoter region of BRCA1, p53, and p21 was increased. We hypothesize RVT by affecting the expression and function of methylation and acetylation enzymes altered the epigenetic modifications on promoter histones that restored expression of these critically important tumor suppressor genes.