Cross‐communication between histone H3 and H4 acetylation and Akt‐mTOR signalling in prostate cancer cells. Issue 7 (30th April 2014)

• Record Type: Journal Article
• Authors: Makarević, Jasmina; Tawanaie, Nassim; Juengel, Eva; Reiter, Michael; Mani, Jens; Tsaur, Igor; Bartsch, Georg; Haferkamp, Axel; Blaheta, Roman A.
• Is Part Of: Journal of cellular and molecular medicine. Volume 18:Issue 7(2014)
• Page Start: 1460
• Page End: 1466
• Publication Date: 2014-04-30
• Subjects: Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.12299
• Languages: English
• ISSNs: 1582-1838

Abstract

<abstract abstract-type="main" id="jcmm12299-abs-0001"> <title>Abstract</title> <p>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/mTOR<sup>high</sup>, aH3/aH4<sup>low</sup>) and tumour‐suppressing signals (Akt/mTOR<sup>low</sup>, aH3/aH4<sup>high</sup>) are activated in parallel. Combined use of an HDAC‐ and mTOR inhibitor might then diminish pro‐tumour effects triggered by the HDAC‐ (Akt/mTOR<sup>high</sup>) or mTOR inhibitor (aH3/aH4<sup>low</sup>) alone.</p> </abstract>