Topic
HDAC8
About: HDAC8 is a research topic. Over the lifetime, 402 publications have been published within this topic receiving 22395 citations. The topic is also known as: CDLS5 & HD8.
Papers published on a yearly basis
Papers
TL;DR: The structure of the histone deacetylase catalytic core is described, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, and it is established that the residues that make up the active site and contact the inhibitors are conserved across the HDAC family.
Abstract: Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth, induce terminal differentiation and prevent the formation of tumours in mice models, and they are effective in the treatment of promyelocytic leukemia Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 352% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA The deacetylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp-His charge-relay systems, and establish the mechanism of HDAC inhibition The residues that make up the active site and contact the inhibitors are conserved across the HDAC family These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents
1,805 citations
TL;DR: Holder deacetylase inhibitors are an important emerging therapy with single-agent activity against multiple cancers, and have significant potential in combination use.
Abstract: Purpose Epigenetic processes are implicated in cancer causation and progression. The acetylation status of histones regulates access of transcription factors to DNA and influences levels of gene expression. Histone deacetylase (HDAC) activity diminishes acetylation of histones, causing compaction of the DNA/histone complex. This compaction blocks gene transcription and inhibits differentiation, providing a rationale for developing HDAC inhibitors. Methods In this review, we explore the biology of the HDAC enzymes, summarize the pharmacologic properties of HDAC inhibitors, and examine results of selected clinical trials. We consider the potential of these inhibitors in combination therapy with targeted drugs and with cytotoxic chemotherapy. Results HDAC inhibitors promote growth arrest, differentiation, and apoptosis of tumor cells, with minimal effects on normal tissue. In addition to decompaction of the histone/DNA complex, HDAC inhibition also affects acetylation status and function of nonhistone protei...
914 citations
TL;DR: It is shown that mammalian Snail requires histone deacetylase (HDAC) activity to repress E-cadherin promoter and that treatment with trichostatin A (TSA) is sufficient to block the repressor effect of Snail.
Abstract: The transcription factor Snail has been described as a direct repressor of E-cadherin expression during development and carcinogenesis; however, the specific mechanisms involved in this process remain largely unknown. Here we show that mammalian Snail requires histone deacetylase (HDAC) activity to repress E-cadherin promoter and that treatment with trichostatin A (TSA) is sufficient to block the repressor effect of Snail. Moreover, overexpression of Snail is correlated with deacetylation of histones H3 and H4 at the E-cadherin promoter, and TSA treatment in Snail-expressing cells reverses the acetylation status of histones. Additionally, we demonstrate that Snail interacts in vivo with the E-cadherin promoter and recruits HDAC activity. Most importantly, we demonstrate an interaction between Snail, histone deacetylase 1 (HDAC1) and HDAC2, and the corepressor mSin3A. This interaction is dependent on the SNAG domain of Snail, indicating that the Snail transcription factor mediates the repression by recruitment of chromatin-modifying activities, forming a multimolecular complex to repress E-cadherin expression. Our results establish a direct causal relationship between Snail-dependent repression of E-cadherin and the modification of chromatin at its promoter.
791 citations
TL;DR: Results with acetylation-defective p53 demonstrate that the critical function of acetylations is not to increase the DNA binding affinity of p53 but rather to promote coactivator recruitment and histoneacetylation.
760 citations
TL;DR: The first crystal structures of a humanHDAC are described: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors, which sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across theHDAC family.
722 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2026 | 1 |
| 2025 | 8 |
| 2024 | 14 |
| 2023 | 70 |
| 2022 | 42 |
| 2021 | 16 |