See also Cancer Treatment See also Methylation and Demethylation
Introduction:
Histone tails are normally positively charged due to the amine groups present on theri lysine and arginine amino acids. These positvely charged residues help the histone tails interact with, and bind to, the negatively charged DNA bacbone. Acetylation, which occurs normally, changes amines to amides. This change neutralizes the positive charge on the histone, thereby decreasing the ability of the affected histone to bind to DNA. This, in turn, permit chromatic expansion and, thus, genetic transcription to occur.
There is evidence that histone acetylation and deacetylation are mechanisms by which transcriptional regulation in a cell is achieved (Grunstein, M. (1997) Nature 389: 249-52). These effects are thought to occur through changes in the structure of chromatin by altering the affinity of histone proteins (e.g., H1, H2A, H2B, H3 and H4) for DNA in the nucleosome. It is believed that when the histone protein are hypoacetylated, there is a greater affinity of the histone to the DNA phosphate backbone. This affinity causes DNA to be tightly bound to the histone and renders the DNA inaccessible to transcriptional regulatory elements and machinery. The regulation of acetylated states occurs through the balance of activity between two enzyme complexes, HAT and HDAC which are covered below.
Histone acetyl transferases (HATs):
1. Introduction:
HATs add acetyl groups to histone (particularly H3 & H4) lysine residues which can eliminate higher order chromatin structures. Histone acetylation tends to destablize chromatin structure, perhaps because adding an acetyl group removes the + charge from lysine, thereby making it difficult for histones to neutralize the charges on DNA. In addition to reducing the interaction between DNA and the histones, HATs may also provide binding sites for proteins that recognize acetylated lysines but not de-acetylated lysines. Decondensed or “open” chromatin is characterized by hyperacetylation of associated histones as well as by increased accessibility to restriction enzymes, nucleases and transcription factors. Histone acetylation may play a role in excision repair of DNA damage. Reports have shown that treatment of fibroblast strains with sodium butyrate, an agent which inhibits histone deacetylase enzymes, results in a 2-3 fold stimulation in repair synthhsis occurring immediately after UV irradiation.
Histone deacetylases(HDACs):
Introduction:
HDAcs remove acetyl groups from the the lysine residues of histone proteins, which has the reverse effect of above (condenses chromatin and prevents gene expression). Histone deacetylation is a major mechanism of methylated DNA silencing. (See US Patent No. 6,541,661 entitled “inhibitors of Histone Deacetylase” provides compounds and methods for inhibiting HDAC enzymes.)
Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups form an epsilon N-acetyl lysine residue on a histone, thereby permitting the histone to wrap DNA more tightly. The action is opposite to the funciton of histone acetyltransferase.
HDACs Inhibitors:
Vorinostate: is an orally bioavaialbe hydroxamate pan-HDAC inhibiotr currently approved in the US for the treatment of cutaneous T-cell lymphoma. Verinostate inhibits a broad spectrum of HDAC enzymes, namely class I (HDACs 1-3) and class IIb (HDACs 6 and 10). Hodge, US 2019/0183870A1)
Entinostate: specifically inhibits class I HDAC enzymes (HDACs 1-3 and 8). (Hodge, US 2019/0183870A1)
Therapeutic applications of HDA inhibitors:
Baopoulos (US 2007/0190022A1) discoses methods of treating cancer by adinistering to a subject an HDAC inhibitor.