Abstract
Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.
Highlights
The mechanisms regulating gene expression involve a series of molecular modifications in DNA and chromatin and are responsible for the response to any type of physiological signaling in the organism [1]
MiDAC is a tetrameric complex that is composed of HDAC1/2, DNTTIP1 and the protein co-repressor MIDEAS (SANT domain associated with mitotic deacetylase) [125,126]
Increasing the expression of antigens present in the tumor and acting as immunomodulators compounds are classified into two large classes, isoform-selective inhibitors and pan-inhibitors, The anticancer activity of HDAC inhibitor (HDACi) comprises different molecular and physiological events such as which act against all class I histone deacetylase (HDAC) [134,190]
Summary
The mechanisms regulating gene expression involve a series of molecular modifications in DNA and chromatin and are responsible for the response to any type of physiological signaling in the organism [1]. The modifications in the histone chains define the compaction or relaxation of chromatin through the recruitment and binding of various specific proteins, functioning as an epigenetic machinery [26] This epigenetic information is an important component in the regulation of gene expression since the breakdown of epigenetic integrity has been associated with different diseases, including cancer [27,28]. The addition of an acetyl group to a lysine residue neutralizes its positive charge on the nitrogen atom, alters the structure of the amino acid and blocks other modifications at this specific site [29] This epigenetic alteration is related to disorders and diseases because of its participation in various physiological processes, acting in synergy with transcription factors, oncoproteins and kinases, affecting protein stabilization and activating or inhibiting gene transcription and DNA repair [30]. 2002 [78] and so far they are the least studied and understood HDACs
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