Vitamin C enhances epigenetic modifications induced by 5-azacytidine and cell cycle arrest in the hepatocellular carcinoma cell lines HLE and Huh7
Background: 5-Azacytidine (5-AZA), a DNA methyl transferase inhibitor, is a clinically used epigenetic drug for cancer therapy. Recently, we have shown that 5-AZA upregulates ten-eleven translocation (TET) protein expression in hepatocellular carcinoma (HCC) cells, which induce active demethylation....
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
30 April 2016
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| In: |
Clinical epigenetics
Year: 2016, Volume: 8, Issue: 1 |
| ISSN: | 1868-7083 |
| DOI: | 10.1186/s13148-016-0213-6 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1186/s13148-016-0213-6 Verlag, Volltext: https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-016-0213-6 
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| Author Notes: | Sahar Olsadat Sajadian, Chaturvedula Tripura, Fazel Sahraneshin Samani, Marc Ruoss, Steven Dooley, Hossein Baharvand and Andreas K. Nussler |
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| 245 | 1 | 0 | |a Vitamin C enhances epigenetic modifications induced by 5-azacytidine and cell cycle arrest in the hepatocellular carcinoma cell lines HLE and Huh7 |c Sahar Olsadat Sajadian, Chaturvedula Tripura, Fazel Sahraneshin Samani, Marc Ruoss, Steven Dooley, Hossein Baharvand and Andreas K. Nussler |
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| 520 | |a Background: 5-Azacytidine (5-AZA), a DNA methyl transferase inhibitor, is a clinically used epigenetic drug for cancer therapy. Recently, we have shown that 5-AZA upregulates ten-eleven translocation (TET) protein expression in hepatocellular carcinoma (HCC) cells, which induce active demethylation. Vitamin C facilitates TET activity and enhances active demethylation. The aim of this study is to investigate whether vitamin C is able to enhance the effect of 5-AZA on active demethylation and to evaluate its consequence in HCC cell lines. Methods: HCC cell lines (Huh7 and HLE) were treated with 5-AZA and vitamin C. After 48 h of treatment, viability (resazurin conversion), toxicity (lactose dehydrogenase (LDH) release), and proliferation ((proliferating cell nuclear antigen (PCNA)) of single- and combined-treated cells were assessed. The effect of the treatment on 5-hydroxymethylcytosine (5hmC) intensity (immunofluorescence (IF) staining), TET, Snail, GADD45B, and P21 mRNA (real-time PCR) and protein expression (Western blot) were investigated. Results: Our results indicated that vitamin C enhances the anti-proliferative and apoptotic effect of 5-AZA in HCC cell lines. By further analyzing the events leading to cell cycle arrest, we have shown for the first time in HCC that the combination of 5-AZA and vitamin C leads to an enhanced downregulation of Snail expression, a key transcription factor governing epithelial-mesenchymal transition (EMT) process, and cell cycle arrest. Conclusions: We conclude that when combined with 5-AZA, vitamin C enhances TET activity in HCC cells, leading to induction of active demethylation. An increase in P21 expression as a consequence of downregulation of Snail accompanied by the induction of GADD45B expression is the main mechanism leading to cell cycle arrest in HCCs. | ||
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