Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

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.

Schedule-Dependent Synergy Between the Histone Deacetylase Inhibitor Belinostat and the Dihydrofolate Reductase Inhibitor Pralatrexate in T-and B-cell Lymphoma Cells in vitro

“…The accumulation of cells in the S-phase as was found in our cells was in line with earlier observations that PLX induces accumulation of DLBCL cells in the S-phase ( Tonner et al, 2006 ). In earlier studies on HDAC combinations ( Eckschlager et al, 2017 ; Verza et al, 2020 ), it was shown that a modulating concentration of the HDAC inhibitor is able to enhance the efficacy of DNA targeted drugs, such as the cross-linker cisplatin, possibly by down regulation of DNA repair enzymes by the HDAC inhibitor. This is in line with the interaction data described in the present study.…”

“…Belinostat (BLS) is a hydroxamic acid-based pan-histone deacetylase (HDAC) inhibitor that inhibits all of the zinc-dependent HDAC enzymes, with high affinity for the Class I, II and IV isozymes ( Eckschlager et al, 2017 ). HDAC inhibition results in an alteration in the degree of histone and non-histone protein acetylation, which in turn affects transcription of genes essential in cellular proliferation, cell cycle and DNA repair ( Verza et al, 2020 ). Hence BLS is an epigenetic drug ( Yeon et al, 2020 ) and is approved for the treatment of PTCL, but may have some activity against B-cell lymphomas as well ( Tula-Sanchez et al, 2013 ).…”

“…HDACs are a group of enzymes responsible for the deacetylation of histones, the core nucleosomal protein. Deacetylation of histones enables the DNA to wrap itself more tightly around the histone ( Eckschlager et al, 2017 ; Verza et al, 2020 ). Inhibition of this event will keep histones in an acetylated state in which the DNA will be more accessible for transcription ( Vandermeers et al, 2013 ).…”

“…The acetylated state allows transcription of proteins involved in cell cycle arrest and other tumor suppressor genes ( Ramalingam et al, 2009 ; Eckschlager et al, 2017 ), enabling an increase in cell death. HDAC inhibition leads to a decrease in the activity of DNA repair enzymes, preventing DNA damage, caused by DNA damaging drugs, being repaired ( Verza et al, 2020 ). We reasoned that the epigenetic inhibition of HDAC would lead to decreased DNA repair, so that DNA damage caused by PLX, would not be repaired.…”

Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

“…The HDACIs are a class of small-molecules that inhibit the activity of Zn 2+ -dependent classical HDACs (class I, II, and class IV HDACs) and promote acetylation of histone and nonhistone protein substrates. Originally, HDACIs were known for their varied cellular effects on cancer cells, such as inhibiting cell proliferation and stimulating differentiation or apoptosis, advocating their usefulness in anticancer drug discovery, and development [80,81]. Now, it is recognized HDACIs induce an array of cellular effects [69,82,83].…”