Targeting histone demethylases in cancer therapy

Abstract

A novel oligoamine analog inhibitor of histone demethylases blocks colon tumor cell growth in association with histone methylation and gene re-expression. It also markedly potentiates the activity of hypomethylating agents in vitro and in vivo, suggesting that histone demethylase inhibitors may represent a valuable addition to the armamentarium of epigenetic agents.

Figure 1

Model of interactions between epigenetic agents in gene re-expression and tumor cell death. Tumor suppressor genes are silenced in transformed cells by multiple mechanisms, including aberrant methylation at promoter regions, mutations in nucleosome remodeling complex proteins, and diverse histone modifications, including acetylation, methylation, phosphorylation, SUMOylation, and glycosylation, among others. Inhibitors of DNMT such as 5-azacytine and 5-aza-2’-deoxycytidine reverse gene methylation and promote re-expression. Analogously, HDAC inhibitors lead to histone acetylation, resulting in a more open chromatin structure, and enhanced gene expression. They can also block the actions of co-repressor complexes. Oligoamine analog inhibitors of histone demethylases i.e., LSD1 induce positive methylation marks on H3K4, accompanied by re-expression of Wnt pathway antagonist genes (SRFPs). Combined exposure of tumor cells with two agents that act at different levels of the epigenome (e.g., HDACIs and hypomethylating agents or hypomethylating agents and histone methyltransferase inhibitors) may be particularly effective in counteracting gene silencing and triggering transformed cell death. Abbreviations: DNMT: DNA methyltransferase; DNMTI (DNA methyltransferase inhibitor); 5-AC: 5-azacytidine; DAC: 5-aza 2’-deoxyazacytine; HDM: histone demethylase; HDMI: histone demethylase inhibitor; HMT: histone methyltransferase; HMTI: histone methyltransferase inhibitor; LSD1: flavin-dependent amine oxidase histone demethylase; SFRPs: secreted frizzled-related proteins; SWI/SNF complex: mating-type switching/sucrose non-fermenting complex.