Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 490, Issue 2, Pages 176-181Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2017.06.017
Keywords
Ten-eleven translocation 2 (TET2); Hypoxia inducible factor-1 alpha (HIF-1 alpha); Ascorbic acid; 5-Hydroxymethylcytosine (5 hmC); Melanoma; Glioblastoma
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Expression and function of Ten-eleven translocation (TET) enzymes, which initiate DNA demethylation by catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine (5 hmC) on methylated DNA, are frequently lost in malignant tissue. This ultimately results in lost expression of methylated tumor suppressor genes. Many malignancies, including melanoma, also aberrantly overexpress the oncogenic hypoxia inducible factor-1 alpha (HIF-1 alpha) transcription factor, however the association between HIF-1 alpha and TET enzyme expression is largely uninvestigated. Interestingly, ascorbic acid, a critical cofactor for optimal TET enzyme function and normoxic regulation of HIF-1 alpha protein stability, is frequently depleted in malignant tissue, and may further contribute to the malignant phenotype. In our studies, we found supplementation of WM9 human metastatic melanoma cells with ascorbic acid significantly increased 5 hmC content, which was abrogated by TET2 knockdown. Moreover, knockdown of HIF-1 alpha increased TET2 gene and protein expression, and further augmented ascorbic acid-induced TET2 dependent 5-hydroxymethylation in both WM9 and T98G glioblastoma cells. Our data provides novel evidence that HIF-1 alpha is involved in regulating TET expression and 5 hmC status of malignant cells. Furthermore, therapeutic intervention to inhibit HIF-1 alpha in conjunction with adjuvant ascorbic acid may promote DNA demethylation and reexpression of critical tumor suppressor genes in malignant cells and warrants further investigation. (C) 2017 Elsevier Inc. All rights reserved.
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