Histone Deacetylase Pathway

Figure1. Histone deacetylase pathway.

Histone deacetylase overview

The orderly regulation of gene transcription is a prerequisite for the maintenance of normal functions of the body's cells. If the transcriptional regulation of the gene is disordered, the cells may become cancerous. Recent studies have found that the occurrence of tumors is closely related to the imbalance between acetylation and deacetylation of core histones. In the organism, a pair of functionally antagonistic proteases is responsible for histone acetylation and deacetylation, namely histone acetyltransferase (HAT) and histone deacetylase (HDAC). The body uses these two enzymes to acetylate and deacetylate the nitrogen-terminal amino acid residues of histones, regulate the structure of chromatin, and regulate gene transcription. Studies have shown that histone deacetylase inhibitors can cause accumulation of acetylated nucleosome histones in vitro and in vivo, increase the expression level of p21 gene, inhibit tumor cell proliferation, induce cell differentiation or apoptosis, and use the treatment of a variety of malignant blood diseases and solid tumors. Researchers have systematically studied the in vivo and extracellular activities of HDAC inhibitors, and some HDAC inhibitors have entered the clinical research stage.

Histone deacetylase family

In mammals, 18 histone deacetylases have been discovered. These enzymes are classified into four types, type I histone deacetylase, type II histone deacetylase, type III histone deacetylase, and type IV histone deacetylase. Type I histone deacetylases, including HDAC1, HDAC2, HDAC3, and HDAC8, are highly homologous to Rpd-3 of S. cerevisiae HDAC. Type II histone deacetylases include HDAC4, HDAC5, HDAC7 and HDAC9, which are highly homologous to the brewer's yeast cell Hda-1. Type III histone deacetylase, also known as longevity protein, is NAD-dependent deacetylation and is associated with the yeast inhibitor Sir-2. Type IV histone deacetylase, the newly identified histone deacetylase, is homologous to human HDAC11. Type I, II, and IV histone deacetylases are a family of primitive enzymes that exhibit highly conserved sequences in prokaryotic and eukaryotic cells. Histone deacetylase 2 contains some specific functional regions. Histone deacetylase 2 is a long chain protein consisting of 488 amino acids. Two adjacent histidine residues form a pocket structure, and two aspartic acid and one histidine constitute a charge relay system containing Zn2+, which together constitute the activation center of histone deacetylase 2. The catalytic domain of histone deacetylase 2 partially overlaps with the N-terminal HDAC junction domain, which contributes to the formation of HDAC dimers. The C-terminal portion contains an IAC (E/D) E structure that interacts with the pocket proteins pRb, p107, and p130. Two amino acid residues in the catalytic domain interact with the ubiquitin ligase Chfr to regulate protein degradation. Histone deacetylases act catalytically, relying directly on the complex of Zn2+ with aspartic acid and histidine to hydrolyze the amide bond. This deacetylation can occur on histones or non-histones. Except for histone deacetylase 8, all type I histone deacetylases do not bind directly to DNA but form a stable polyprotein structure that exerts its catalytic action. These complexes can activate the deacetylase activity of type I histone deacetylases and mediate silencing of specific sites by interacting with other regulatory proteins. In mammals, histone deacetylase 1 interacts with histone deacetylase 2, and together with a variety of proteins constitutes the catalytic core of its inhibition. The protein complex with histone deacetylase as the core includes a nuclear small body plastic deacetylase (NURD) complex, a co-repressor element 1 silencing transcription factor complex, a MiDAC complex, and a SIN3 complex. The size of the complex (200 kDa ~ 2 MDa) and the number of subunits (3 ~ 14) are quite different. Histone deacetylases bind to these proteins, causing changes in chromosomal remodeling or chromosomal binding and providing a platform for coordinated deacetylation with other chromosomal regulatory mechanisms.

Histone deacetylase pathway

  1. Histone deacetylase pathway cascade
    We will describe the cascade of different histone deacetylation. HDAC6 has a unique non-histone substrate specificity, and its substrate mainly includes α-tubulin, actin, and heat shock protein 90 (Hsp90). These proteins are expressed in the cytosol and are consistent with the subcellular localization of HDAC6, but under certain conditions, HDAC6 also appears in the nucleus. α-tubulin is the first confirmed HDAC6 deacetylation substrate, and its reversible acetylation state can significantly affect the stability and function of microtubules. For example, overexpression of HDAC6 results in a low acetylation level of tubulin and promotes chemotaxis cell movement; conversely, inhibition of HDAC6 function leads to hyperacetylation of tubulin and excessive accumulation of focal adhesions, thereby inhibiting fibroblast movement. In addition to regulating tubulin-dependent cellular movement, HDAC6 also alters the acetylation state of actin, affecting its ability to bind to fibrillar actin, thereby modulating actin-dependent cellular movement. The researchers also found that HDAC6 regulates the acetylation status of Hsp90. Since Hsp90 can increase the activity and stability of many important signaling proteins, the regulation of HDAC6 acetylation by HDAC6 is also an important factor affecting cell signaling. In addition to the activity of deacetylase, HDAC6 also binds to ubiquitin. Under normal conditions, misfolded proteins can be effectively degraded by the proteasome. When the proteasome is damaged, the misfolded protein forms a polymer. This polymer produces an HDAC6 binding site under the action of deubiquitinating enzyme ataxin-3. HDAC1 and HDAC2 play important regulatory roles in the differentiation and maturation of neuronal progenitor cells, and cortical neuron arrangement disorder occurs in double knockout mice. The phenomenon suggests that HDAC2 and HDAC1 facilitate the migration and proper alignment of cells in the brain. MacDonald et al. found that the expression of HDAC2 was observed in the embryonic progenitor cells of the embryonic mouse of 13.5 d and was up-regulated in the neuronal and mature neurons formed after division. In the embryonic mouse of 18.5 d, the level of HDAC2 in the superficial layer of the cerebral cortex was higher, and the neurons in this area were more mature than the deep layer. In addition, the HDAC2 expression is higher in adult mouse neuronal progenitor cells and their dividing neuroblasts and mature neurons. These studies suggest that HDAC2 is involved in the regulation of neuronal differentiation genes and the maturation process of neurons, both in embryonic development and in adult brains. During the development and differentiation of glial cells, there was no obvious abnormality in the development of astrocytes in the brain of HDAC1 and HDAC2 double knockout mice.
  2. Pathway regulation
    With an in-depth study of the relationship between HDAC and cancer, it has been found that inhibition of HDAC activity can cause accumulation of acetylated histones in cells, increase the expression levels of genes such as p21 and p53, and inhibit tumor cells. These genes can induce cell differentiation and/or apoptosis. HDAC inhibitors also exhibit anti-metabolic and anti-angiogenic activities in both in vitro and in vivo experiments. Glycoprotein RECK has a down-regulation of matrix metalloproteinases, which inhibits tumor metastasis and angiogenesis. HDAC inhibitors increase RECK expression, inhibit matrix metalloproteinase activity, and metastasize cancer cells. Since the 1990s, a variety of HDAC inhibitors have been obtained, and a variety of HDAC inhibitors have been introduced into clinical trials. Studies have shown that they can inhibit the proliferation of various tumor cells, induce tumor cell differentiation and/or apoptosis, and are a class of antitumor drugs with broad application prospects. The structure of the hydroxamic acid HDAC inhibitor consists of a ring, a fatty chain, and a hydroxamic acid. It mainly includes trichostatin, SAHA, NVP-LAQ824, pyroxamide, CBHA, oxamflatin, scriptaid, MM232, etc. It is the most studied and most intensive HDAC inhibitor. HDAC inhibitors such as short-chain fatty acids are relatively simple in structure, mainly including N-butyric acid, valproic acid, and phenyl butyric acid and their salts. N-butyric acid is a short-chain fatty acid produced by anaerobic fermentation of dietary fiber in human colon, which is widely found in fruits, vegetables, and milk. Studies have shown that N-butyric acid can increase the expression level of p21 gene in human gastric cancer cell lines and inhibit the growth of cancer cells. Cyclic peptides: Cyclic peptides HDAC inhibitors mainly include trapoxin, FK228, apicidin, HC-toxin, WF3161-CHAP53 and the like. These compounds contain a cyclic tetrapeptide structure in the molecule, and compounds such as trapoxin and HC-toxin contain an epoxy ketone structure at the end of the carbon chain. The structures of HDAC inhibitors MS-275, depudecin, Cl-994, CS-055, etc. are different from the above three types of structures and are a special type of HDAC inhibitors. MS275 has anti-proliferative activity against various tumor cells such as osteosarcoma, neuroblastoma, medulloblastoma, retinoblastoma and malignant rod-shaped tumor.
  3. Relationship with disease
    Studies have shown that M. tuberculosis H37Rv infection of human macrophages can cause an increase in histone deacetylase 1 expression, accompanied by a significant decrease in histone H3 acetylation. In the process of M. tuberculosis infection, IL-12 recruits histone deacetylase 1, and then the hypoacetylation of histone H3 inhibits the expression of this gene, thereby inhibiting the Th-1 response. Therefore, inhibition of histone deacetylase 1 expression may play an important role in activating the Th-1 type immune response and exerting anti-tuberculosis effects.
    Abnormal expression of HDAC in cancer cells has been reported in many kinds of literature, and abnormal expression of histone deacetylase 2 is present during tumorigenesis. In certain cancer cells, consumption of histone deacetylase 2 causes cancer cell growth to stop and apoptosis. Histone deacetylase 2 inhibits INPP5F and GSK3β/APC-mediated degradation of β-catenin, a process that plays a key role in histone deacetylase 2 expression and tumor development. In addition, histone deacetylase 2 silences the expression of the apoptotic precursor, cysteine protease 9, and the activation of proteins APAF1 and NOXA. Histone deacetylase 2 inhibits the expression of the tumor suppressor gene p53 and promotes MYC expression. Histone deacetylase 2 regulates the expression of these proteins, hinders the process of apoptosis, and can lead to adverse effects such as cell cycle disorders.


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