LAUSR

In cancer, where the balance between proliferation and differentiation is disturbed, changes in the epigenome occur, some of which present as potential therapeutic targets. Changes in DNA methylation and histone deacetylation have been investigated for some time and inhibitors of DNA methylases (e.g. azacytidine, decetabine) and of histone deacetylases (HDACs) (e.g. vorinostat, romidepsin) are used clinically, mainly for cancers of the hemopoietic system. Lessons can be learned from these studies where the basic concept was that inhibition of transcription by DNA methylation or by elimination of the active acetyl mark resulted in silencing of tumor suppressors (p21, BRACA1, p53). In fact, the changes in DNA methylation that occur in cancer are complex, with large domains being hypomethylated [1]. Moreover, multiple enzymes can deacetylate histones, thus affecting multiple networks, but which networks and which HDACs are important for inhibition of cancer growth is relatively unexplored. Thus, while screening libraries for inhibitors of an enzyme activity is an attractive option, where family members share the same enzyme activity and active domain, selective targeting of a specific protein rather than an enzyme family is preferable. In considering the lysine demethylase 5 (KDM5) demethylases, as targets in cancer, it is important to note that, as members of the larger JmjC class of Fe(II) and 2-oxoglutarate-dependent demethylases, they share the catalytic site with all proteins in this group (Figures 1 and 2(a)). Therefore, screening for inhibitors of KDM5 demethylases requires serious investigation into the following: (i) The function of the individual KDM5 enzymes in a range of cancers and normal cells. (ii) The feasibility of developing inhibitors with some selectivity for the individual proteins and the use of inhibitors to investigate function. The availability of the crystal structure of the KDM5 family members A, B, and C and studies on their interaction with the target histone mark is already guiding the development of more specific KDM5 inhibitors [2–4].