Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer

Abstract

Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO levels generally have protective effects, higher NO concentrations induce cytotoxic/cytostatic actions. In recent years, evidences have been accumulated unveiling S-nitrosylation as a major NO-dependent post-translational mechanism ruling gene expression. S-nitrosylation is a reversible, highly regulated phenomenon in which NO reacts with one or few specific cysteine residues of target proteins generating S-nitrosothiols. By inducing this chemical modification, NO might exert epigenetic regulation through direct effects on both DNA and histones as well as through indirect actions affecting the functions of transcription factors and transcriptional co-regulators. In this light, S-nitrosylation may also impact on cancer cell gene expression programs. Indeed, it affects different cell pathways and functions ranging from the impairment of DNA damage repair to the modulation of the activity of signal transduction molecules, oncogenes, tumor suppressors, and chromatin remodelers. Nitrosylation is therefore a versatile tool by which NO might control gene expression programs in health and disease.

Valosin-containing protein acts as a target and mediator of S-nitrosylation in the heart through distinct mechanisms

“…By adding a nitrosyl group (NO-) to reactive cysteine thiols, SNO can profoundly influence protein-protein interactions and subsequent modifications, such as phosphorylation, acetylation, ubiquitination, and disulfide bond formation [ 2 ]. This regulatory mechanism plays a multifaceted role in protein stability, transcriptional regulation, DNA damage repair, cellular growth, and apoptosis [ [4] , [5] , [6] ]. In addition, research has demonstrated that SNO not only acts as a scavenger of nitric oxide (NO), preventing its interaction with reactive oxygen species (ROS) but also serves to protect cysteine thiols from ROS-mediated oxidation [ 7 ]; thus, it has been considered as an emerging paradigm of redox signaling protecting cells against oxidative stress in the hearts.…”

Nitric Oxide Prevents Glioblastoma Stem Cells’ Expansion and Induces Temozolomide Sensitization

“…In the context of cancer, the influence of NO extends to cell cycle, apoptosis, mitogenic pathways, angiogenesis, invasion, and DNA integrity [27,28]. Thanks to its gaseous nature [29], NO can diffuse through cellular membranes, affecting tumor cells' phenotype and behavior [30,31], as well as tumor microenvironment (TME) [32].…”