Cross‐communication between histone H3 and H4 acetylation and Akt‐m TOR signalling in prostate cancer cells

Abstract 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 R apamycin (m TOR ) 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 m TOR signalling and epigenetic events regulated by HDAC . DU ‐145 prostate cancer cells were treated with insulin‐like growth factor ( IGF ) to activate the Akt‐m TOR cascade or with the HDAC ‐inhibitor valproic acid ( VPA ) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, m TOR , 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 m TOR and the epigenetic machinery. IGF activated m TOR , Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGF r blockade and knock‐down blocked the Akt‐m TOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up‐regulated histone acetylation, but also activated m TOR ‐Akt signalling. HDAC 1 and 2 knock‐down revealed that the interaction with the m TOR system is initiated by histone H3 acetylation. HDAC ‐m TOR communication, therefore, is apparent whereby tumour‐promoting (Akt/m TOR high , aH3/aH4 low ) and tumour‐suppressing signals (Akt/m TOR low , aH3/aH4 high ) are activated in parallel. Combined use of an HDAC ‐ and m TOR inhibitor might then diminish pro‐tumour effects triggered by the HDAC ‐ (Akt/m TOR high ) or m TOR inhibitor (aH3/aH4 low ) alone.