Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells
Open accessAbstract
The Ten Eleven Translocation (TET) enzymes have been found to be mutated in both diffuse large B-cell (DLBCL) and peripheral T-cell (PTCL) lymphomas resulting in DNA hypermethylation. Recent studies in embryonal stem cells showed that ascorbic acid (AA) is a cofactor for TET with a binding site at the catalytic domain, and enhances TET activity. We hypothesized that AA could potentially enhance TET activity in lymphoma cells to cause DNA demethylation, reactivate expression of tumor suppressor genes and enhance chemosensitivity. We demonstrate in vitro that AA treatment of DLBCL and PTCL cells using AA concentrations achievable intravenously increased TET activity leading to DNA demethylation. This epigenetic effect is independent of hydrogen peroxide. AA treatment increased the expression of SMAD1, a tumor suppressor gene known to be suppressed by methylation, and increased chemosensitivity of lymphoma cells. Twenty-nine percent (10/34) of unselected lymphoma patients had plasma AA levels that were deficient suggesting an additional clinical mechanism of TET hypofunction. These data indicate that AA has the potential to modify TET function in lymphoma and enhance chemosensitivity. In addition, the AA deficiency seen in some patients may further impair TET function and contribute to resistance. Clinical trials testing intravenous AA with chemotherapy are warranted.
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In some lymphomas that often carry TET mutations, ascorbate in vitro boosted TET activity, causing DNA demethylation, more tumour suppressor expression, and greater chemosensitivity.
“In certain types of lymphomas where TETs are frequently mutated, ascorbate treatment in vitro increased TET activity, leading to DNA demethylation, increased expression of tumour suppressor genes and increased chemosensitivity69.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [69]
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- Authors
- Shenoy, N., Bhagat, T., Nieves, E., Stenson, M., Lawson, J., Choudhary, G. S., Habermann, T., Nowakowski, G., Singh, R., Wu, X., Verma, A., & Witzig, T. E.
- Affiliations
- Mayo Clinic (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Shenoy, N
- Witzig, T E
- Venue
- Blood Cancer Journal
- Published
- 2017-07-21
- Volume
- 7
- Issue
- 7
- Pages
- e587-e587
- ISSN
- 2044-5385 (ISSN-L)
- PMC
- PMC5549257
- OpenAlex
- W2738179899
- Cited by
- 111
- References
- 40
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 9 · 2023: 19 · 2022: 14 · 2021: 14 · 2020: 15 · 2019: 12 · 2018: 12 · 2017: 1
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Blood Cancer Journal (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA97274)
- National Cancer Institute (P50CA097274)
- National Center for Research Resources (S10RR029398)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- TET enzymes, vitamin C, DNA demethylation, diffuse large B-cell lymphoma, peripheral T-cell lymphoma, epigenetic modulation, Smad1, tumor suppressor gene reactivation, chemosensitivity, DNA hypermethylation, scurvy, chemoresistance
- MeSH terms
- Ascorbic Acid, Humans, Mixed Function Oxygenases, Proto-Oncogene Proteins, Up-Regulation, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse, Cell Line, Tumor
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