• Open Access

Targeting histone deacetylases for the treatment of disease

Authors

  • M. W. Lawless,

    1. Centre for Liver Disease, School of Medicine and Medical Science, Mater Misericordiae University Hospital – University College Dublin, Dublin, Ireland
    2. Hepatology Research Division and Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, St James's Hospital, James's Street, Dublin, Ireland
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  • S. Norris,

    1. Hepatology Research Division and Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, St James's Hospital, James's Street, Dublin, Ireland
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  • K. J. O’Byrne,

    1. Translational Cancer Research Group, Department of Clinical Medicine, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin, Ireland
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  • S. G. Gray

    Corresponding author
    1. Translational Cancer Research Group, Department of Clinical Medicine, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street, Dublin, Ireland
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*Correspondence to: Steven G. GRAY, Translational Cancer Research Group, Department of Clinical Medicine, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, James's Street Dublin 8, Ireland.
Tel.: 0035318963620
E-mail: sgray@stjames.ie

Abstract

  • • Introduction
  • • HATs/HDACs and the pro-inflammatory environment
  • • HATs/HDACs and endoplasmic reticulum (ER) stress
  • • The potential role of histone deacetylase inhibitors in the treatment of cancer
    • - Non-small cell cancer (NSCLC)
      • - In vitro evidence for targeting HDACs in NSCLC
      • - Combinatorial therapies involving HDi in NSCLC
    • - Hepatocellular carcinoma (HCC)
      • - In vitro evidence for the use of HDi in liver cancer
      • - Combinatorial treatments involving HDi in hepatoma
  • • Potential role of histone deacetylase inhibitors in the treatment of diabetes
    • - Disease models, knockouts and assays
    • - Pancreatic islet protection using histone deacetylase inhibitors
    • - Additional in vitro evidence
    • - Stem cells, HDACs and histone deacetylase inhibitors
  • • The potential role of histone deacetylase inhibitors in the treatment of neurodegenerative conditions
    • - Neuronal traits are modulated by HDAC/REST complexes
    • - E2F, HDACs and neuronal survival mechanisms
    • - HDACs play important roles in stem cell neuronal differentiation
  • • Histone deacetylase inhibitors
    • - SAHA (vorinostat)
    • - Phenylbutyrate
    • - Valproic acid
    • - AN-9
    • - CI-994
    • - Romidepsin
    • - MS-275
    • - LBH589 (panobinostat)
    • - MGC D0103
  • • Caveats
    • - Do HDAC inhibitors target genes or help chaperone activity as their primary response?
  • • Final comments

Abstract

The ‘histone code’ is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular ‘code’ recognized and used by non-histone proteins to regulate specific chromatin functions. One modification, which has received significant attention, is that of histone acetylation. The enzymes that regulate this modification are described as lysine acetyltransferases or KATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The pro-inflammatory environment is increasingly being recognized as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential and current development of histone deacetylases for the treatment of diseases for which a pro-inflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the pro-inflammatory environment.

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