Expression of Adenoviral E1A in Transformed Cells as an Additional Factor of HDACi-Dependent FoxO Regulation

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.

Ras Participates in the Regulation of the Stability of Adenoviral Protein E1A via MAP-kinase ERK

“…It has been shown that E1A sensitizes tumor cells with respect to HDIs (SAHA, TSA) more effectively than with respect to other chemotherapy drugs (5-fluorouracil, cisplatin, etoposide, or paclitaxel) [ 13 ]. However, as we have shown earlier, HDI induced degradation of E1A [ 15 ].…”

“…Показано, что сенсибилизирующий эффект E1A в отношении цитотоксического действия ИГД (SAHA, TSA) сильнее, чем других химиотерапевтических препаратов (5-фторурацил, цисплатин, этопозид, паклитаксел) [13]. Однако, как показано нами ранее, действие ИГД приводит к деградации Е1А [15].…”

“…Ранее нами были отмечены различия в интенсивности ИГД-индуцированной деградации белка E1A в клетках, экспрессирующих Ras дикого типа или мутантный белок, что дало нам возможность выдвинуть предположение о роли белка Ras в регуляции стабильности E1A [15]. Малая GTP-аза Ras является ключевым регулятором клеточного роста [22].…”

“…Previously, we showed that there was a difference in the dynamics of HDI-induced E1A degradation in cells expressing wild-type Ras or a mutant Ras protein [ 15 ]. These observations suggest that there is a role played by the Ras protein in the regulation of E1A stability.…”

Diverse roles of FOXO family members in gastric cancer

“…However, stress-induced FOXO1 acetylation also arrests FOXO1 ubiquitination and prevents FOXO1 degradation through the ubiquitin-proteasome pathway[ 48 ]. Importantly, acetylation of FOXOs is a reversible process and can be eliminated by histone acetyltransferases and histone deacetylases (HDACs)[ 49 , 50 ]. For example, Sirt1, a class III HDAC, can deacetylate FOXOs and increase their transcription[ 47 ].…”