Abstract
Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an important role in the epigenetic regulation of gene expression. Histone modification is controlled by the balance between histone acetyltransferase and (HAT) and histone deacetylase (HDAC) enzymes. Imbalance between the activities of these two enzymes is associated with various forms of cancer. Histone deacetylase inhibitors (HDACi) regulate the activity of HDACs and are being used in cancer treatment either alone or in combination with other chemotherapeutic drugs/radiotherapy. The Food and Drug Administration (FDA) has already approved four compounds, namely vorinostat, romidepsin, belinostat, and panobinostat, as HDACi for the treatment of cancer. Several other HDACi of natural and synthetic origin are under clinical trial for the evaluation of efficiency and side-effects. Natural compounds of plant, fungus, and actinomycetes origin, such as phenolics, polyketides, tetrapeptide, terpenoids, alkaloids, and hydoxamic acid, have been reported to show potential HDAC-inhibitory activity. Several HDACi of natural and dietary origin are butein, protocatechuic aldehyde, kaempferol (grapes, green tea, tomatoes, potatoes, and onions), resveratrol (grapes, red wine, blueberries and peanuts), sinapinic acid (wine and vinegar), diallyl disulfide (garlic), and zerumbone (ginger). HDACi exhibit their antitumor effect by the activation of cell cycle arrest, induction of apoptosis and autophagy, angiogenesis inhibition, increased reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells. This review summarizes the HDACs classification, their aberrant expression in cancerous tissue, structures, sources, and the anticancer mechanisms of HDACi, as well as HDACi that are either FDA-approved or under clinical trials.
Highlights
Cancer is the second leading cause of death worldwide and caused 8.8 million deaths in 2015.Globally, 1 out of 6 deaths is because of cancer
Knockdown of HDAC2 in cervical cancer causes increased apoptosis and the differentiated phenotype of cells associated with increased p21Cip1/WAF1 expression that was independent of p53 [43]
histone deacetylase (HDAC) 7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis, suggesting that HDAC7 may represent a rational target for anti-angiogenesis in cancer [58]
Summary
Cancer is the second leading cause of death worldwide and caused 8.8 million deaths in 2015. 22 of of 32 changes, such as translocation, amplification, deletion and point mutation, it involves epigenetic thethe pattern of gene withoutwithout changing underlying. Methylation of DNA, histone protein modifications and non-coding RNA-mediated gene the majorare epigenetic changes, reversible in nature [4]. N-terminals (histone(histone tails) of core flexible and the nucleosome particle. Acetylation and deacetylation of N-terminal group residues could a role in gene expression [7,8]. Acetylation of lysine residue occursacetylation in non-histone proteins, such as condensation andN-terminal downregulation of gene expression. N-terminal of lysine residue cytoplasmic proteins, transcription responsible for alteration in genefactors expression and other occurs in non-histone proteins, suchfactors as cytoplasmic proteins, transcription responsible for cellular processes [10]. Alteration in gene expression and other cellular processes [10]
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