Abstract
HDAC inhibitors (HDACIs) induce irreversible cell cycle arrest and senescence in mouse embryonic fibroblasts transformed with E1A and c-Ha-Ras oncogenes (E1A+Ras cell line). The aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS). Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. It's known that HDACs regulate the ROS-dependent FoxO factors, which are responsible for cell growth, proliferation, and longevity. The characteristic ROS increase during aging may be responsible for the decreased HDAC activity, which facilitates the senescent-like phenotype. The objective of this study was to investigate the impact of FoxO transcription factors on HDACIs-induced senescence of E1A+Ras oncogenes transformed cells. This study shows the specific time-dependent effect of HDACI sodium butyrate treatment on FoxO proteins in E1A+Ras cells. Indeed, short-term treatment with NaB results in FoxO activation, which takes place through nuclear translocation, and accompanied by accumulation of such ROS scavengers as MnSOD and SOD2. However, prolonged treatment leads to extensive FoxO degradation and increased intracellular levels of ROS. This degradation is connected with NaB-induced activation of Akt kinase. All of these findings establish that one of the possible mechanism involved in NaB-induced senescence of transformed cells is mediated through down-regulation of FoxO transcription factors and ROS accumulation.
Highlights
Diversity of forkhead box protein O (FoxO) functions is impressively wide and comprises such aspects of cell life as metabolism, DNA repair, cell death, senescence etc
There are several lines of evidence supporting that FoxO inhibition is important for Akt-induced Reactive Oxygen Species (ROS) accumulation
Our data show that sodium butyrate (NaB) regulates FoxO transcription factors on the post-transcriptional level, in time-dependent manner, activating FoxOs and triggering their nuclear translocation after short-term treatment
Summary
Diversity of FoxO functions is impressively wide and comprises such aspects of cell life as metabolism, DNA repair, cell death, senescence etc. This diversity arises from multi-level regulation, which in turn is greatly dependent on the cell context. Acetylation, like the rest of post-transcriptional modifications, is an essential part of FoxO regulation. FoxO proteins bind to coactivators and corepressors causing changes in FoxO acetylation level. Acetylation and deacetylation of FoxO have complex effect on the transcription of target genes and this effect seems to be promoter-specific. It has been revealed that enzymes participating in acetylation of FoxO are involved in acetylation of histones [2]. It should be mentioned that deacetylation can facilitate FoxO degradation, since the same lysine residues are used for acetylation and polyubiquitination [4]
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