Dot1L mediated histone H3-(Lys 79) methylation activates the p21Waf1 gene and functions as a biomarker for apoptotic sensitivity towards HDAC inhibitors

A33 Histone decacetylase inhibitors (HDACi) are promising new anti-cancer agents with tumor specific selectivity over non-transformed cells. However, there is a clear need to select the right patients to receive treatment with these new agents. We have identified an epigenetic marker, methylation of histone H3 at lysine 79 (K79), which was found to be predictive for apoptotic response to HDAC inhibition. Both, lack of basal K79 methylation-and HDACi mediated methylation response are predictive of sensitivity to apoptosis after treatment of cells with HDACi. The increase in lysine 79-methylation of histone H3 appears specific for HDACi induced apoptosis and is mediated by the histone methyltransferase Dot1L. We further show by chromatin-immunoprecipitation (ChIP)-analyses and Dot1L gene knockdown studies that histone (K79)-methylation response occurs at the proximal promoter region of the p21 gene leading to its activation. In summary, assessing the (K79) histone methylation status or ex vivo response to a HDACi of tumor specimens in clinical trials with HDAC inhibitors may help to select patients that will respond to HDACi treatment.