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 Rapamyc
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.
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Author:Jasmina Makarević, Nassim Tawanaie, Eva Jüngel, Michael Reiter, Jens Mani, Igor Tsaur, Georg Bartsch, Axel Haferkamp, Roman A. Blaheta
URN:urn:nbn:de:hebis:30:3-372030
URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124028/
DOI:http://dx.doi.org/10.1111/jcmm.12299
ISSN:1582-4934
ISSN:1582-1838
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24779401
Parent Title (English):Journal of cellular and molecular medicine
Publisher:Wiley-Blackwell
Place of publication:Hoboken, NJ
Document Type:Article
Language:English
Date of Publication (online):2014/04/30
Date of first Publication:2014/04/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2015/04/29
Tag:HDAC; cross-communication; mTOR; prostate cancer cells
Volume:18
Issue:7
Pagenumber:7
First Page:1460
Last Page:1466
Note:
Copyright © 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.
HeBIS PPN:368976289
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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