Abstract
Abstract
One of the common contributors to the pre-disposition of most human cancers is inappropriate activation of AKT due to loss of its negative regulator PTEN. Activated AKT regulates changes in metabolic processes such as acetyl-CoA production that impacts chromatin. AKT phosphorylates a wide variety of histone modulating enzymes including acetyltransferases and methyltransferases resulting in their hyperactivation or inhibition. Therefore, understanding the impact of AKT inhibition on global histone modification would be ideal to identify novel histone modifiers regulated by AKT. We performed unbiased and comprehensive profiling of histone modifications in prostate specific PTEN knockout mice treated with an AKT inhibitor (Perifosine, 10mg/kg body weight daily for 4 weeks) and observed that AKT inhibition significantly induces di and tri methylation of H3K4, concomitant with reduction acetylation of H3K9. Changes in other histone modifications such as H3K36 and H3K79 methylation and acetylation were not observed. Mechanistically, we observed that AKT inihibiton reduces the expression of H3K4 methylation related histone demethylases KDM5 family, especially KDM5B expression at transcriptional level. Similar observations were noted at translational level also. To further understand the transcriptional regulation of KDM5B by AKT we focused on miR-137 and miR-138 as these have been shown to transcriptionally regulate H3K4 demethylases. We observed that AKT activation negatively regulated miR-137 but not miR-138 levels, which further transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 di and tri methylation levels but failed to change AKT phosphorylation. Genetic knockdown of AKT or inhibition of AKT phosphorylation increased miR137 and reduced both KDM5B levels. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR137. Our data identify a mechanism by which PI3K/AKT signaling modulates the prostate cancer epigenome through regulating H3K4 methylation and KDM5B expression. Additional studies that assess the impact of AKT inhibiton on genome occupancy of H3K4 methylation will help in the identification of targets and devise novel strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors that are currently in clinical development.
Citation Format: Mohammad Imran Khan, Suvasmita Rath, Qateeb Khan, Vaqar M. Adhami, Hasan Mukhtar. AKT mediates transcriptional regulation of H3K4 demethylase in PTEN null prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3344. doi:10.1158/1538-7445.AM2017-3344