Nitric oxide regulates gene expression in cancers by controlling histone posttranslational modifications [PrimeView]

Dynamic changes in histone posttranslational modifications (PTMs) are important regulators of chromatin structure and gene transcription in both normal and disease settings. Herein, we describe a novel signaling mechanism of nitric oxide (•NO) by demonstrating its ability to modulate gene expression via alteration of histone PTMs. Having established that •NO exposure induced differential expression of approximately 6500 genes, we set out to determine if there was an epigenetic component to their regulation. •NO exposure led to alterations in the global levels of acetyl and methyl modifications at numerous lysine residues on core histones H3 and H4. Residues H3K9me2/ac were examined further and determined to have differential distribution at various loci throughout the genome in response to •NO. Changes in the enrichment levels of H3K9me2/ac at specific genes correlated with changes in the expression levels of their transcripts. Molecular mechanisms contributing to phenotypic outcomes in •NO-associated cancers remain to be well understood since traditional modes of •NO-signaling do not explain a large proportion of its impact on tumor cell behavior. Our results reveal that •NO drives a significant amount of gene expression changes epigenetically by changing the distribution of numerous histone marks. Cultured cells were treated with 500uM DETA/NO to examine the effects of a physiologically relevant •NO concentration on gene expression. A total of two untreated biological replicates and two •NO-treated biological replicates were harvested. The untreated samples served as control against which comparisons were made to elucidate •NO-mediated changes in the gene expression.