The GCN5: its biological functions and therapeutic potentials

Abstract

General control non-depressible 5 (GCN5) or lysine acetyltransferase 2A (KAT2A) is one of the most highly studied histone acetyltransferases. It acts as both histone acetyltransferase (HAT) and lysine acetyltransferase (KAT). As an HAT it plays a pivotal role in the epigenetic landscape and chromatin modification. Besides, GCN5 regulates a wide range of biological events such as gene regulation, cellular proliferation, metabolism and inflammation. Imbalance in the GCN5 activity has been reported in many disorders such as cancer, metabolic disorders, autoimmune disorders and neurological disorders. Therefore, unravelling the role of GCN5 in different diseases progression is a prerequisite for both understanding and developing novel therapeutic agents of these diseases. In this review, we have discussed the structural features, the biological function of GCN5 and the mechanical link with the diseases associated with its imbalance. Moreover, the present GCN5 modulators and their limitations will be presented in a medicinal chemistry perspective.

GCN5 contributes to intracellular lipid accumulation in human primary cardiac stromal cells from patients affected by Arrhythmogenic cardiomyopathy

“…Indeed, several small molecule that inhibit GCN5 (i.e. MB‐3) have been discovered and already taken into consideration for the treatment of different pathologies associated with GCN5 dysregulation like type 2 diabetes, insulin resistance, metabolic disease and syndrome, dyslipidaemia, obesity or overweight, neurodegenerative diseases, heart failure, muscle diseases and improvement of exercise endurance capacity 39,40 …”

“…intensity: integrated intensity; dens. Sum: densitometric sum metabolic disease and syndrome, dyslipidaemia, obesity or overweight, neurodegenerative diseases, heart failure, muscle diseasesand improvement of exercise endurance capacity 39,40. Therefore, the MB-3 compound was tested in the ACM context.…”

High-resolution Ribosome Profiling Reveals Translational Selectivity for Transcripts in Bovine Preimplantation Embryo Development

“…For example, LRWD1 is a subunit of the origin recognition complex (ORC) and plays a role in heterochromatin organization and cell cycle control (20)(21)(22)(23). KAT2A (also known as GCN5), a histone acetyltransferase, and SUV39H1, a histone methyltransferase that trimethylates lysine 9 of histone H3, are most highly studied histone enzymes and play pivotal roles in the epigenetic landscape and chromatin modification (24,25). Given that a hallmark feature of a competent oocyte is chromatin condensation, the surprisingly highly selective translation of these genes in oocytes (both GV and MII) and the likely role of the translated proteins in maintaining the repressive heterochromatic state suggest that, in combination, these genes may have important function in the epigenetic control of bovine oocyte competence.…”

Acetylation in Tumor Immune Evasion Regulation

“…General control non-depressible 5 (GCN5) mainly responsible for acetylation of H3K27, is the first histone acetyltransferase to be characterized in saccharomyces cerevisiae. GCN5 is highly expressed in a variety of human cancers and promotes cancer progression by participating in the acetylation of many non-histone proteins ( Haque et al, 2021 ). An example is in prostate cancer, where upregulated GCN5 downregulates Egr-1 expression via the PI3K/PTEN/Akt signaling pathway, negatively affecting IL-6-induced prostate cancer cell metastasis and epithelial-mesenchymal transition (EMT) ( Shao et al, 2018 ).…”