HDAC6

Official Full Name

histone deacetylase 6

Organism

Homo sapiens

GeneID

10013

Background

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains which appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription. [provided by RefSeq, Jul 2008]

Synonyms

HD6; JM21; CPBHM; KDAC6; PPP1R90;

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Detailed Information

Histones are one of the important components which constitute the chromosome of eukaryotes. Acetylation and deacetylation of histones regulate gene expression through key transcriptional modifications. Histone acetyltransferases (HATS) and histone deacetylases (HDACS) regulate post-translational modifications by the acetylation and the deacetylation of the ε-amino group of lysine residues in histone tails and some non-histone proteins. HDAC6, a unique cytoplasmic deacetylase, targets tubulin, cortactin and HSP90, thus it can regulate cell adhesion, motility and chaperone function. HDAC6 can use tubulin as a substrate and regulate the balance of tubulin acetylation and deacetylation. These effects play an important role in the microtubule network. Relevant research has shown that acetylation and deacetylation of histones are of significant importance in tumor genesis and progression. Inhibition of HDACS has become a promising direction for cancer therapy.

Physiological function

HDAC6 regulates diverse important intracellular biological processes. It effects the growth, migration and death of cells. A recent study found that HDAC6 can also deacetylate peroxiredoxin which is involved in the regulation of redox reactions in vivo. HDAC6 which plays a great role in misfolded protein degradation can be regarded as a target for protein conformational disorders. As a misfolded protein is harmful, cells can clear away it by the way of a molecular chaperon, ubiqutin-proteasomes system (UPS) and autophagy-lysosome pathway (ALP). For a long time, UPS and ALP have been regarded as two parallel degradation pathways, but recent research shows that HDAC6 can form a tripolymer through the Znf-UBP combined with the ubiquitin-misfolded protein and dynein motor binding motif. The tripolymer can be degraded by ALP. Therefore, HDAC6 can control misfolded proteins through regulation of ALP and UPS.

HDAC6 and neurological diseases

It is commonly accepted that HDAC6 affects the occurrence and development of neurological diseases by diverse pathways, such as the formation of aggresomes, autophagy increase, and clearing away misfolded protein. Neurological diseases consist of Alzheimer disease, Parkinson’s disease (PD), Huntington’s disease, and Oculopharyngeal muscular dystrophy. Related work reveals that PD is related with graceful degradation and death of dopamine (DA) neurons, HDAC6 can promote the formation of α-synuclein complex, and the latter can prevent DA neurons from the damage of oligomers. Recent research suggests that aggresomes combined with misfolded protein is the mainly pathologic feature of neurological diseases. HDAC6 can regulate either the formation of aggresome or autophagy as a component of aggresomes. Central nervous system (CNS) injury is another neurological disease characterized by insufficient axonal regeneration and oxidative stress-induced neurodegeneration. Genetic and pharmacological approaches are employed to demonstrate the role of HDAC6 in CNS injury, and this fact reveals that inhibition of HDAC6 can promote regeneration of neurons in CNS injury. Thus, HDAC6 can also be regarded as a target for potential nontoxic therapy of CNS trauma.

HDAC6 Figure 1. The role of HDAC6 in various processes related to neurodegeneration.

HDAC6 and cancer

Expression profiling analysis, with cDNA microarray in MCF-7 cells, suggested that the HDAC6 gene is an estrogen-regulated gene. Estrogens play a key role in the normal growth of mammary glands, as well as in the development of estrogen-dependent breast cancer. The estrogen-mediated up-regulation of HDAC6 demonstrates that there might be a link between the levels of HDAC6 expression and metastasis of breast cancer that may be useful in the prognosis of patients.

The overexpression of HDAC6 has been identified in various other cancer cell lines and mouse tumor models. Compared with benign lesions and immortalized ovarian surface epithelium cell lines, the expression levels of HDAC6 in ovarian cancer cells and tissues were higher in low-grade and high-grade ovarian carcinomas. HDAC6 expression was also upregulated in primary oral squamous cell lines and its level of expression correlated with primary tumor stage. In another study, HDAC6 was consistently overexpressed in primary acute myeloid leukemia (AML) blasts and in some myeloblastic cell lines. In addition, extensive use of HDAC inhibitors has elucidated mechanisms of cancer cell growth, development and metastasis, and this line of work continues to be pursued leading, hopefully, to a cure for cancer and alleviation of patients’ suffering.

References:

Haakenson J , Zhang X . HDAC6 and Ovarian Cancer. International Journal of Molecular Sciences, 2013, 14(5):9514-9535.
Yang, Penghui. HDAC6: Physiological function and its selective inhibitors for cancer treatment. Drug Discoveries & Therapeutics, 2013, 7(6).
Aldana-Masangkay G I, Sakamoto K M. The role of HDAC6 in cancer. Biomed Research International, 2011, 2011(1110-7243):875824.
Simões-Pires, et al. HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? Molecular Neurodegeneration. 2013, 8:7

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