Histone methylases as novel drug targets. Focus on EZH2 inhibition. Catherine BAUGE1,2,#, Céline BAZILLE1,2,3, Nicolas GIRARD1,2, Eva LHUISSIER1,2, Karim BOUMEDIENE1,2 1 Normandie Univ, France 2 UNICAEN, EA4652 MILPAT, Caen, France 3 Service d’Anatomie Pathologique, CHU, Caen, France # Correspondence and copy request: Catherine Baugé,
[email protected], EA4652 MILPAT, UFR de médecine, Université de Caen Basse-Normandie, CS14032 Caen cedex 5, France; tel: +33 231068218; fax: +33 231068224 1 ABSTRACT Posttranslational modifications of histones (so-called epigenetic modifications) play a major role in transcriptional control and normal development, and are tightly regulated. Disruption of their control is a frequent event in disease. Particularly, the methylation of lysine 27 on histone H3 (H3K27), induced by the methylase Enhancer of Zeste homolog 2 (EZH2), emerges as a key control of gene expression, and a major regulator of cell physiology. The identification of driver mutations in EZH2 has already led to new prognostic and therapeutic advances, and new classes of potent and specific inhibitors for EZH2 show promising results in preclinical trials. This review examines roles of histone lysine methylases and demetylases in cells, and focuses on the recent knowledge and developments about EZH2. Key-terms: epigenetic, histone methylation, EZH2, cancerology, tumors, apoptosis, cell death, inhibitor, stem cells, H3K27 2 Histone modifications and histone code Epigenetic has been defined as inheritable changes in gene expression that occur without a change in DNA sequence. Key components of epigenetic processes are DNA methylation, histone modifications and variants, non-histone chromatin proteins, small interfering RNA (siRNA) and micro RNA (miRNA).