Cross-communication between histone H3 and H4 acetylation and Akt-mTOR signalling in prostate cancer cells

Molecular tumour targeting has significantly improved anti-cancer protocols. still,the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. combined mammalian target of rapamycin (mtor) and histone deacetylase (hdac) inhibition has been shown not only to enhance anti-tumour potential,but also to prevent resistance development seen under mono-drug therapy. this investigation was designed to evaluate whether cross-communication exists between mtor signalling and epigenetic events regulated by hdac. du-145 prostate cancer cells were treated with insulin-like growth factor (igf) to activate the akt-mtor cascade or with the hdac-inhibitor valproic acid (vpa) to induce histone h3 and h4 acetylation (ah3,ah4). subsequently,mtor,rictor,raptor,p70s6k,akt (all: total and phosphorylated),h3 and h4 (total and acetylated) were analysed by western blotting. both techniques revealed a link between mtor and the epigenetic machinery. igf activated mtor,rictor,raptor,p70s6k and akt,but also enhanced ah3 and ah4. inversely,igfr blockade and knock-down blocked the akt-mtor axis,but simultaneously diminished ah3 and ah4. vpa treatment up-regulated histone acetylation,but also activated mtor-akt signalling. hdac1 and 2 knock-down revealed that the interaction with the mtor system is initiated by histone h3 acetylation. hdac-mtor communication,therefore,is apparent whereby tumour-promoting (akt/mtorhigh,ah3/ah4low) and tumour-suppressing signals (akt/mtorlow,ah3/ah4high) are activated in parallel. combined use of an hdac- and mtor inhibitor might then diminish pro-tumour effects triggered by the hdac- (akt/mtorhigh) or mtor inhibitor (ah3/ah4low) alone. © 2014 the authors.