Vitamin C promotes decitabine or azacytidine induced DNA hydroxymethylation and subsequent reactivation of the epigenetically silenced tumour suppressor CDKN1A in colon cancer cells
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Christian Gerecke1, Fabian Schumacher1,2, Alexander Edlich1, Alexandra Wetzel1, Guy Yealland1, Lena Katharina Neubert1, Bettina Scholtka1, Thomas Homann1 and Burkhard Kleuser1,3
1Institute of Nutritional Science, Department of Nutritional Toxicology, University of Potsdam, Nuthetal, Germany
2Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
3NutriAct – Competence Cluster Nutrition Research Berlin-Potsdam, Germany
Burkhard Kleuser, email: firstname.lastname@example.org
Keywords: vitamin C; tumor suppressors; epigenetics; TET; DNA hydroxymethylation
Received: May 16, 2018 Accepted: August 04, 2018 Published: August 28, 2018
Epigenetic silencing of tumour suppressor genes is a key hallmark of colorectal carcinogenesis. Despite this, the therapeutic potential of epigenetic agents capable of reactivating these silenced genes remains relatively unexplored. Evidence has shown the dietary antioxidant vitamin C (ascorbate) acts as an inducer of the ten-eleven translocation (TET) dioxygenases, an enzyme family that catalyses a recently described mechanism of DNA demethylation linked to gene re-expression. In this study, we set out to determine whether vitamin C can enhance the known anti-neoplastic actions of the DNA-demethylating agents decitabine (DAC) and azacytidine (AZA) in colorectal cancer cells. Administration of vitamin C alone significantly enhanced global levels of 5-hydroxymethyl-2’-deoxycytidine (5-hmdC), without altering 5-methyl-2’-deoxycytidine (5-mdC), as would be expected upon the activation of TET dioxygenases. Concomitant treatment of vitamin C with either AZA or DAC resulted in an unexpectedly high increase of global 5-hmdC levels, one that administration of any these compounds alone could not achieve. Notably, this was also accompanied by increased expression of the tumour suppressor p21 (CDKN1A), and a significant increase in apoptotic cell induction. Our in vitro data leads us to hypothesize that the reactivation of genes in colorectal cancer cells by AZA or DAC can be improved when the 5-hmdC levels are simultaneously increased by the TET activator vitamin C. The dual administration of demethylating agents and vitamin C to colorectal cancer patients, a demographic in which vitamin C deficiencies are common, may improve responses to epigenetic therapies.
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