Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

Abstract

Acetylation, a reversible epigenetic process, is implicated in many critical cellular regulatory systems including transcriptional regulation, protein structure, activity, stability, and localization. Lysine acetylation is the most prevalent and intensively investigated among the diverse acetylation forms. Owing to the intrinsic connections of acetylation with cell metabolism, acetylation has been associated with metabolic disorders including cancers. Yet, relatively little has been reported on the features of acetylation against the cancer hallmarks, even though this knowledge may help identify appropriate therapeutic strategies or combinatorial modalities for the effective treatment and resolution of malignancies. By examining the available data related to the efficacy of lysine acetylation against tumor cells and elaborating the primary cancer hallmarks and the associated mechanisms to target the specific hallmarks, this review identifies the intrinsic connections between lysine acetylation and cancer hallmarks and proposes novel modalities that can be combined with HDAC inhibitors for cancer treatment with higher efficacy and minimum adverse effects.

The role of protein acetylation in carcinogenesis and targeted drug discovery

“…For histone acetylation to exert their biological functions, they also need to be combined with specific recognition proteins. Acetylated lysine in a protein will provide a reading site, recruit proteins with special structural domains, affect biological functions such as gene replication, gene transcription, and repair after DNA damage, and jointly participate in the regulation of gene expression ( 8 ). Recognition proteins can contain multiple different recognition domains that cooperate with PTM sites.…”

“…Recognition proteins can contain multiple different recognition domains that cooperate with PTM sites. Studies have shown that lysine-containing acetylation modification sites can be specifically recognized by proteins such as bromodomains, dual-PHD finger domains, and YEATS domains ( 8 ).…”

“…Acetylation modification is the process of covalently binding acyl-CoA compounds to specific amino acid sites of proteins under the action of acetyltransferase, generally binding to lysine residues ( 8 ). This process can also be reversed by deacetylases.…”

“…Acetylation processes in different organelles are independent of each other. For example, acetyl-CoA in mitochondria and acetyl-CoA outside mitochondria are independent of each other ( 8 ). Acetylation in mitochondria plays an important role in biological processes such as the tricarboxylic acid cycle and fatty acid oxidation ( 9 , 10 ).…”

HDACi: The Columbus’ Egg in Improving Cancer Treatment and Reducing Neurotoxicity?

“…The balance of HDACs’ and HATs’ activity in the cell is fundamental for the achievement of the correct cellular function [ 12 ] and, for this reason, these enzymes need to be strictly regulated in the cells ( Figure 1 ). Any mutation or any change in their expression, or in the expression of the genes they regulate, could even lead to tumor development and cause neurological disorders, such as Huntington’s (HD) and Alzheimer’s diseases (AD) [ 13 , 14 ].…”