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Expression of Adenoviral E1A in Transformed Cells as an Additional Factor of HDACi-Dependent FoxO Regulation
Alisa Morshneva, Olga Gnedina, Tamara Marusova1
1Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia.
Abstract:
The adenoviral early region 1A (E1A) protein has proapoptotic and angiogenic activity, along with its chemosensitizing effect, making it the focus of increased interest in the context of cancer therapy. It was previously shown that E1A-induced chemosensitization to different drugs, including histone deacetylases inhibitors (HDACi), appears to be mediated by Forkhead box O (FoxO) transcription factors. In this study, we explore the relationship between E1A expression and the modulation of FoxO activity with HDACi sodium butyrate (NaBut). We show here that the basal FoxO level is elevated in E1A-expressing cells. Prolonged NaBut treatment leads to the inhibition of the FoxO expression and activity in E1A-expressing cells. However, in E1A-negative cells, NaBut promotes the transactivation ability of FoxO over time. A more detailed investigation revealed that the NaBut-induced decrease of FoxO activity in E1A-expressing cells is due to the NaBut-dependent decrease in E1A expression. Therefore, NaBut-induced inhibition of FoxO in E1A-positive cells can be overcome under unregulated overexpression of E1A. Remarkably, the CBP/p300-binding domain of E1Aad5 is responsible for stabilization of the FoxO protein. Collectively, these data show that the expression of E1A increases the FoxO stability but makes the FoxO level more sensitive to HDACi treatment.
Insights
Adenoviral E1A protein stabilizes Forkhead box O (FoxO) transcription factors. However, E1A expression enhances FoxO sensitivity to histone deacetylase inhibitors like sodium butyrate, impacting cancer therapy strategies.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Adenoviral E1A protein exhibits pro-apoptotic and angiogenic properties, relevant to cancer therapy.
- E1A-induced chemosensitization is linked to Forkhead box O (FoxO) transcription factors.
- Histone deacetylase inhibitors (HDACi) are investigated for their role in cancer treatment.
Purpose of the Study:
- To investigate the interplay between adenoviral E1A protein expression and Forkhead box O (FoxO) transcription factor activity under HDAC inhibition.
- To elucidate the mechanism by which HDAC inhibitors modulate FoxO activity in the presence or absence of E1A.
Main Methods:
- Cellular assays to measure FoxO protein levels and transcriptional activity.
- Treatment of cells with sodium butyrate (NaBut), a histone deacetylase inhibitor.
- Manipulation of E1A expression levels, including unregulated overexpression.
Main Results:
- E1A expression elevates basal FoxO levels and enhances FoxO protein stability.
- Sodium butyrate (NaBut) inhibits FoxO activity in E1A-expressing cells by reducing E1A levels.
- In E1A-negative cells, NaBut promotes FoxO transactivation.
- Unregulated E1A overexpression can overcome NaBut-induced FoxO inhibition.
Conclusions:
- Adenoviral E1A protein stabilizes FoxO, but this stabilization paradoxically increases FoxO sensitivity to HDAC inhibitors.
- The CBP/p300-binding domain of E1A is crucial for FoxO protein stabilization.
- Understanding this E1A-FoxO-HDACi interaction is vital for developing targeted cancer therapies.
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