Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone modulating enzymes resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin related events is essential. Here, we report that AKT inhibition in prostate specific PTEN knockout mice significantly induces di- and tri-methylation of H3K4 with concomitant reduction in H3K9 acetylation. Mechanistically, we observed that AKT inhibition reduces expression of the H3K4 methylation specific histone demethylases KDM5 family, especially KDM5B expression at transcriptional levels. Further, we observed that AKT negatively regulates miR-137 levels, which transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 methylation levels but failed to change AKT phosphorylation. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR-137. Our data identify a mechanism by which AKT kinase modulates the prostate cancer epigenome through regulating H3K4 methylation. Additional studies on AKT inhibition mediated induction of H3K4 methylation will help in designing strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors.
Molecular cancer therapeutics. 2018 Nov 16 [Epub ahead of print]
Mohammad Imran Khan, Abid Hamid, Suvasmita Rath, Bushra Ateeq, Qateeb Khan, Imtiaz A Siddiqui, Vaqar Mustafa Adhami, Hani Choudhry, Mazin A Zamzami, Hasan Mukhtar
Dermatology, University of Wisconsin-Madison ., Dermatology, University of Wisconsin-Madison., Biological Sciences & Bioengineering, Indian Institute of Technology Kanpur., Department of Biochemistry, King Abdulaziz University.