Contributed equally as senior authors.
Cross-communication between histone H3 and H4 acetylation and Akt-mTOR signalling in prostate cancer cells
Article first published online: 30 APR 2014
© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Journal of Cellular and Molecular Medicine
Volume 18, Issue 7, pages 1460–1466, July 2014
How to Cite
Makarević, J., Tawanaie, N., Juengel, E., Reiter, M., Mani, J., Tsaur, I., Bartsch, G., Haferkamp, A. and Blaheta, R. A. (2014), Cross-communication between histone H3 and H4 acetylation and Akt-mTOR signalling in prostate cancer cells. Journal of Cellular and Molecular Medicine, 18: 1460–1466. doi: 10.1111/jcmm.12299
- Issue published online: 30 JUL 2014
- Article first published online: 30 APR 2014
- Manuscript Accepted: 18 MAR 2014
- Manuscript Received: 25 NOV 2013
- Alfons und Gertrud Kassel-Stiftung
- HDAC ;
- 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.