Time-dependent modulation of FoxO activity by HDAC inhibitor in oncogene-transformed E1A+Ras cells

Alisa Morshneva; Olga Gnedina; Svetlana Svetlikova; Valery Pospelov; Maria Igotti; Alisa Morshneva; Olga Gnedina; Svetlana Svetlikova; Valery Pospelov; Maria Igotti

doi:10.3934/genet.2018.1.41

AIMS Genetics

2018, Volume 5, Issue 1: 41-52. doi: 10.3934/genet.2018.1.41

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Research article Special Issues

Time-dependent modulation of FoxO activity by HDAC inhibitor in oncogene-transformed E1A+Ras cells

Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia

Received: 01 November 2017 Accepted: 01 February 2018 Published: 08 February 2018

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.
- histone deacetylase inhibitor (HDACi),
- sodium butyrate,
- FoxO,
- oxidative stress,
- ROS,
- Akt,
- nuclear shuttling
Citation: Alisa Morshneva, Olga Gnedina, Svetlana Svetlikova, Valery Pospelov, Maria Igotti. Time-dependent modulation of FoxO activity by HDAC inhibitor in oncogene-transformed E1A+Ras cells[J]. AIMS Genetics, 2018, 5(1): 41-52. doi: 10.3934/genet.2018.1.41

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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.

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