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Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders

An Addendum to this article was published on 27 February 2015

Key Points

  • Epigenetic deregulation can underpin the onset and progression of several human diseases.

  • The expression and/or function of histone deacetylases (HDACs) is often perturbed in cancer, neurological syndromes and immune disorders.

  • HDACs can be effectively targeted using small-molecule chemical compounds, and more selective agents are currently being developed and further tested.

  • Histones are not the only substrates of HDACs, and altered acetylation of diverse cellular proteins may be important in disease aetiology and the response to HDAC inhibitors.

  • HDACs function as the catalytic subunits of large multiprotein complexes, and the molecular and biological consequences of HDAC inhibition need to be assessed in this context.

  • HDAC inhibitors have been approved for the treatment of certain haematological malignancies and are being clinically evaluated alone and in combination with other agents for efficacy in other cancer settings, in neurological diseases and in immune disorders such as autoimmunity.

Abstract

Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators — histone deacetylases (HDACs) — and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.

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Figure 1: Epigenetic writers, readers and erasers.
Figure 2: Leukaemia-associated fusion proteins recruit HDACs.
Figure 3: The role of HDAC isoforms in regulating immunity.
Figure 4: Structure of HDAC inhibitors.

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Acknowledgements

R.W.J. is a Principal Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia and his research is supported by the NHMRC Program and Project Grants, Cancer Council Victoria, the Leukaemia Foundation of Australia and the Victorian Cancer Agency. The research of K.J.F. was supported by a postdoctoral fellowship from Cancer Council Victoria. The authors thank S. Mincci for helpful comments and advice.

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Correspondence to Ricky W. Johnstone.

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The Johnstone laboratory has received grant funding from Novartis and Merck for studies using panobinostat and vorinostat, respectively. R.W.J. has received speaker's honoraria from Novartis. K.J.F. declares no competing interests.

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Broad specificity HDAC inhibitors (PDF 110 kb)

Glossary

Histone deacetylases

(HDACs). A family of 18 proteins in humans, consisting of class I proteins (HDAC1, HDAC2, HDAC3 and HDAC8), class IIa proteins (HDAC4, HDAC5, HDAC7 and HDAC9), class IIb proteins (HDAC6 and HDAC10), class III proteins (sirtuins 1–7) and class IV proteins (HDAC11). These enzymes remove acetyl groups from lysine on histones and other proteins.

Epigenetic modifications

Reversible, heritable genetic changes that occur without changes in DNA sequence.

Chromatin remodelling

An alteration in chromatin structure that affects the nuclease sensitivity of a region of chromatin. Accomplished by covalent modification of histones and/or the action of ATP-dependent remodelling complexes.

Epigenetic writers

Enzymes such as histone acetyltransferases, methylases and kinases, which covalently modify the amino-terminal 'tails' of histone proteins, and DNA methyltransferases, which modify the DNA itself.

Epigenetic erasers

Enzymes such as histone deacetylases, phosphatases, deubiquitylases and demethylases that reverse covalent modifications within the amino-terminal 'tails' of histone proteins.

Epigenetic readers

Proteins containing chromodomains, bromodomains, Tudor domains and DNA methyl-binding domains that recognize specific histone marks and recruit other chromatin modifiers and remodelling proteins to alter chromatin architecture and function.

Tauopathies

A class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain.

Regulatory T cell

(TReg cell). A T cell type that suppresses the immune responses of other cells to maintain tolerance to self-antigens and abrogate autoimmune disease.

Polypharmacological molecules

Single drug molecules that bind to multiple targets.

Oncogene addiction

The reliance of tumours on a single dominant oncogene for growth and survival, so that inhibition of this specific oncogene is sufficient to halt the neoplastic phenotype.

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Falkenberg, K., Johnstone, R. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 13, 673–691 (2014). https://doi.org/10.1038/nrd4360

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