The therapeutic uses of chromatin-modifying agents

Abstract

In contrast to genetic aberrations, epigenetic aberrations can be reversed by the use of histone acetyltransferase (HAT), histone deacetylase (HDAC), SIRT, or histone methyltransferase (HMT) inhibitors. A well-known HDACi, suberoylanilide hydroxamic acid, has been recently approved for the treatment of cutaneous T cell lymphoma, and a number of HDACi are in clinical trials as anticancer drugs. In addition, HDACi could be useful in antimalarial and antifungal therapies and can reactivate the HIV-1 expression in latent cellular reservoirs, thus suggesting the use in a combination therapy with highly active antiretroviral therapy. HDACi have also been reported to have anti-inflammatory effects through inhibition of cytokines and key transcription factors, and to ameliorate the phenotypes in animal models of neurological disorders. HDACi can also reactivate the γ-globin gene for the treatment of β-thalassaemia, and recently were shown to relieve morphological and functional effects of muscular dystrophia. Dysfunction of HAT enzymes is also often associated with several diseases, including cancer; thus, the HATi can represent new chemical entities for the development of new drugs. Only a few HMTi have been described to date, but these small molecules could be a useful scaffold to discovering new highly active and enzyme-selective compounds to develop as therapeutics.

Keywords::

• cancer
• chromatin remodelling
• epigenetics
• histone acetyltransferase
• histone deacetylase
• histone methyltransferase

Acknowledgements

This work was partially supported by grants from AIRC 2006 and PRIN 2006 protocol 2006038137_0056.