Molecules in focus
Molecular basis of the anti-cancer effects of histone deacetylase inhibitors

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Abstract

Histone deacetylase inhibitors comprise a variety of natural and synthetic compounds, which have in common that they inhibit enzymes that mediate the removal of acetyl groups from a range of proteins, including nucleosomal histones. Histone deacetylase inhibitors have anti-cancer activities in vitro and in vivo and are used in the clinic for the treatment of advanced cutaneous T cell lymphoma. The molecular pathways targeted by these compounds are discussed with an emphasis on the effects of these compounds on retinoic acid signaling.

Section snippets

HDACs and protein acetylation

Epigenetics is defined as the reversible heritable changes in gene activity that occur without a change in the sequence of nuclear DNA. Chromatin consists of DNA wrapped around histone proteins, organized in structural units termed nucleosomes (Richmond and Davey, 2003). Hence, the term epigenetics often, but not exclusively, refers to modifications of the histone proteins. The architecture and compaction of chromatin is modified by covalent posttranslational modifications of the histones.

HDAC inhibitors

HDAC inhibitors (HDACIs) are a diverse group of compounds that induce, to a variable extent, growth arrest, differentiation or apoptosis in vitro and growth arrest of tumors in mouse models. Treatment of cancer cells with HDACI induces histone hyperacetylation and changes in a variety of proteins associated with proliferation and apoptosis (Johnstone, 2002, Minucci and Pelicci, 2006).

Molecules of a relatively wide range of chemical structures are able to inhibit the activities of HDACs (Minucci

HDACI and cutaneous T cell lymphoma

Cutaneous T cell lymphomas (CTCLs) encompass a heterogeneous group of rare extranodal lymphoproliferative disorders (Kim et al., 2005, Siegel et al., 2000). Primary CTCLs are characterized by the localization of the clonally derived, malignant lymphocytes to the skin at presentation (Siegel et al., 2000). The most common form of CTCL, mycosis fungoides (MF), is indolent but may transform to large cell lymphoma or evolve into a leukemic variant, Sézary syndrome (SS) (Kim et al., 2005). The

HDACI: mechanisms of action

Which signaling pathways are particularly affected by pharmacological serum concentrations of HDACI? Answer to these question may assist in the development of combination therapies to enhance treatment outcomes by optimizing the regulation, shutdown or activation of the targeted pathway. As for HDACI, we do not know the key target(s) for HDACI action, because many non-histone protein substrates could be instrumental in mediating the anti-cancer effects of HDACIs. Alternatively, the simultaneous

Acknowledgements

Grant support: Centre for Biomedical Genetics, Cancer Genomics Centre and the Dutch Cancer Society (KWF).

We apologize to the authors whose research articles could not be cited due to space constraints.

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