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Review

Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics

¹ Research Centre and Department of Medicine, Hôtel-Dieu du Centre hospitalier de l'Université de Montréal; and Departments of ² Medicine and ³ Biology and Cellular Pathology, Université de Montréal, Montréal, Québec, Canada

Requests for reprints: Danuta Balicki, Hôtel-Dieu du Centre hospitalier de l'Université de Montréal, Pavillon Masson, 3850, rue Saint-Urbain, Montréal, Québec, Canada H2W 1T7. Phone: 514-890-8000 ext. 15518; Fax: 514-412-7204. E-mail: danuta.balicki{at}umontreal.ca

Over the past few years, the histone deacetylase (HDAC) inhibitors have occupied an important place in the effort to develop novel, but less toxic, anticancer therapy. HDAC inhibitors block HDACs, which are the enzymes responsible for histone deacetylation, and therefore they modulate gene expression. The cellular effects of HDAC inhibitors include growth arrest and the induction of differentiation. Early successes in cancer therapeutics obtained using these drugs alone or in combination with other anticancer drugs emphasize the important place of posttranslational modifications of histones in cancer therapy. Histone tail modifications along with DNA methylation are the most studied epigenetic events related to cancer progression. Moreover, extranuclear functions of histones have also been described. Because HDAC inhibitors block HDACs and thereby increase histone acetylation, we propose a model wherein exogenous acetylated histones or other related acetylated proteins that are introduced into the nucleus become HDAC substrates and thereby compete with endogenous histones for HDACs. This competition may lead to the increased acetylation of the endogenous histones, as in the case of HDAC inhibitor therapy. Moreover, other mechanisms of action, such as binding to chromatin and modulating gene expression, are also possible for exogenously introduced histones. [Mol Cancer Ther 2008;7(4):740–8]

⁴ U.S. Food and Drug Administration; http://www.fda.gov/.

⁵ U.S. NIH http://clinicaltrials.gov/.

⁶ A. Hadnagy, R. Beaulieu, D. Balicki, unpublished data.

⁷ M. Kaouass, A. Hadnagy, S. Mansour, R. Beaulieu, D. Balicki. Post-translational modifications of histone H2A are pivotal in its inhibition of human breast cancer cell proliferation via senescence. Poster presentation at San Antonio Breast Cancer Symposium, 2006.

⁸ A. Hadnagy, M. Kaouass, S. Mansour, R. Beaulieu, D. Balicki, in preparation.

⁹ A. Hadnagy, M. Kaouass, S. Mansour, R. Beaulieu, D. Balicki, in preparation.

Received 11/26/07; revised 2/ 7/08; accepted 2/15/08.