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HDAC Family

Epigenetics refers to the regulation of gene expression via posttranslational modification of protein complexes associated with DNA, without alterations in the DNA sequence. The basic structure of chromatin consists of the nucleosome, which comprises a 146 bp of DNA wrapped around an octamer of core histones. Histone proteins compact massive amounts of genomic DNA into a size and structure that can be easily housed in the eukaryotic nucleus. These proteins are post-translationally modified by, among others, lysine acetylation and ubiquitination, serine phosphorylation, sumoylation and methylation of arginines and lysines.

The post-translational modifications of greatest interest in this field are acetylation and deacetylation. These processes are regulated by two groups of enzymes with opposite activities: histone acetyltransferases (HATs) and histone deacetylases (HDACs). The former catalyzes the transfer of an acetyl group from acetyl-co-A to the e-amino site of lysine, neutralizing the positive charge on histones and results in an open chromatin that frequently leads to increased DNA transcription. HDACs deacetylate lysine residues allow interactions between negatively charged DNA and histone proteins, resulting in a closed chromatin conformation and repressed transcription.

Overview of the HDAC family

In mice and humans, the 18 HDAC enzymes are grouped into four classes. Classical HDACs (class I, II and IV) share sequence similarity and are dependent on Zn2+ for enzymatic activity, whereas the class III sirtuins act through a distinct NAD+-dependent mechanism. The class III HDACs (sirtuins) are structurally related to yeast SirT2, and there is increasing evidence that they are critical transcriptional regulators.

Class I HDACs (HDAC1, 2, 3 and 8) show similarity to yeast RPD3. They are usually localized to the nucleus because of the presence of a nuclear localization sequence and, with the exception of HDAC3, the absence of a nuclear export signal. Class I HDACs have been most widely studied in their classical role as histone modifiers and transcriptional repressors. The class II enzymes show homology to yeast HDA1 and have been subdivided into class IIa (HDAC4, 5, 7 and 9) and IIb (HDAC6 and 10) based on domain organization. Class IIa HDACs possess N-terminal domains that interact with transcription factors, such as the myocyte enhancer factor (MEF) 2 family. They also possess C-terminal nuclear export signals, which enable shuttling between the nucleus and cytoplasm. Class IIb HDACs (HDAC6 and HDAC10) are distinguished from the class IIa sub-family in possessing tandem deacetylase domains, although the second domain of HDAC10 is reported to be nonfunctional. HDAC6 is unique amongst the classical HDAC family in that it is predominantly cytoplasmic, whereas HDAC10 is found in both the nucleus and cytoplasm. HDAC11 is the sole class IV HDAC (Figure 1).

Figure 1. The classical HDAC family is divided into class I, IIa, IIb and IV.

Regulation of innate immunity by HDACs

A substantial body of evidence has documented roles for HDACs in innate immune pathways. Some studies have linked specific HDAC enzymes to myeloid development. During differentiation of human monocytes to macrophages, HDAC5 is upregulated. Additionally, by interacting with the transcription factor PU.1 and blocking expression of target genes, HDAC3 negatively regulates myeloid cell differentiation. HDACs also regulate mature macrophage and dendritic cell (DC) function by controlling inflammatory mediator production [e.g. cytokines, chemokines and matrix metalloproteinases (MMPs)]. In particular, TLR and IFN signaling pathways are modulated by HDACs in these cells (Figure 2).

Figure 2. Regulation of key innate immune pathways by HDACs and HATs.

The biology of HDAC in cancer

Blocking of apoptosis and differentiation as well as the stimulation of angiogenesis, proliferation, and metastasis are commonly described as hallmarks of cancer and known to be regulated by epigenetic mechanisms including histone acetylation (Figure 3). During tumorigenesis, the global pattern of histone acetylation is changed. For example, cancer cells undergo a loss of acetylation at H4K16, suggesting a crucial role of HDAC activity in establishing the tumor phenotype.

There are various mechanisms leading to a deregulated HDAC activity observed in many cancer types. HDACs can be mutated, changed in their expression levels, or aberrantly recruited in tumor cells. The involvement of HDACs in cancer development has been initially demonstrated for hematological malignancies, where aberrant recruitment of HDAC-containing complexes to specific promoters by fusion proteins resulting from chromosomal translocations leads to abnormalities in differentiation and proliferation of myeloid cells. Structural mutations affecting HDAC expression and/or activity appear to be rare in tumors. To date, the only mutation identified in an HDAC gene is a frameshift in the HDAC2 gene, leading to the loss of HDAC2 protein and activity in human endometrial and colon cell lines. Strikingly, numerous clinical studies in cancer patients have established that the most prevalent alteration of HDAC function in tumors is overexpression. Increased mRNA, as well as protein levels for different HDAC family members, has been reported for a wide variety of human malignancies.

Figure 3. HDACs regulate various hallmarks of cancer.

HDAC inhibitors

HDAC inhibitors are a diverse group of small molecule drugs that induce a broad range of effects on cancer cells. These drugs inhibit HDAC enzymes, and there has been an expanding interest in developing these drugs as anti-cancer agents particularly, as they have a remarkable effect on tumor-cell proliferation compared with non-malignant cells. This suggests that there may be a clinical therapeutic window. From a clinical perspective, there are now a large number of clinical trials with these agents that have completed and are ongoing. Currently, vorinostat and romidepsin have been approved by the Food and Drug Administration (FDA) for treating advanced and refractory cutaneous T-cell lymphoma (CTCL).

HDAC inhibitors mediate cell death through several pathways. These include cell growth arrest, effects on DNA repair and mitosis, induction of apoptosis, anti-angiogenic effects and effects on the misfolded protein response (MPR) pathway. HDAC inhibitors also induce autophagy, although this may be a mechanism of resistance rather than cell death. The classification of HDAC inhibitors is based on their chemical structures. Broadly, these are subdivided into short-chain fatty acids, cyclic tetrapeptides, hydroxamic acids, aliphatic acids and benzamides.

Summary and outlook

HDACs have many histone and nonhistone substrates involved in crucial cellular processes in normal development and cancer. During the multistep process of tumorigenesis, individual HDAC family members contribute to the hallmarks of cancer by blocking differentiation and apoptosis as well as inducing proliferation, angiogenesis, and metastasis. Therefore, it is not surprising that several HDAC family members are frequently overexpressed or aberrantly recruited in various tumor types. Because of the extensive effects of different HDACs on a plethora of substrates, HDACs represent attractive drug targets for cancer treatment. HDAC inhibitor-caused acetylation leads to both changes in gene expression and functional modifications of nonhistone proteins, thereby triggering antitumor pathways. Cancer cells accumulate a variety of defects in proteins that control cell proliferation and survival and it was shown that pan-HDAC inhibitors attack the cancer cell at several levels leading to broad-spectrum antitumor effects. Furthermore, fast cycling tumor cells with multiple defects seem to be more sensitive to HDAC inhibitor treatment than normal cells, which are more likely to compensate for the inhibitory effects.

References:

  1. Witt O, et al. HDAC family: What are the cancer relevant targets?. Cancer Letters, 2009, 277(1):8-21.
  2. Khan O, La Thangue N B. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunology & Cell Biology, 2012, 90(1):85-94.
  3. Shakespear M R, et al. Histone deacetylases as regulators of inflammation and immunity. Trends in Immunology, 2011, 32(7):335-43.
  4. Hagelkruys A, et al. The biology of HDAC in cancer: the nuclear and epigenetic components. Histone Deacetylases: the Biology and Clinical Implication. Springer Berlin Heidelberg, 2011:13.
  5. Haberland M, et al. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Reviews Genetics, 2009, 10(1):32-42.
  6. Baek Y S, et al. Identification of novel transcriptional regulators involved in macrophage differentiation and activation in U937 cells. Bmc Immunology, 2009, 10(1):1-15.
  7. Marks P A. The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opinion on Investigational Drugs, 2010, 19(9):1049.
For research use only. Not intended for any clinical use.

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