Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma
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DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.
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Reduced IDH2 expression causes epigenetic dysfunction through loss of 5-hydroxymethyl-cytosine in melanoma.
“whereas its downregulation leads to epigenetic dysfunction via the loss of 5-hydroxymethyl-cytosine in melanoma (Lian et al., 2012).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Lian et al., 2012
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- Authors
- Lian, C. G., Xu, Y., Ceol, C., Wu, F., Larson, A., Dresser, K., Xu, W., Tan, L., Hu, Y., Zhan, Q., Lee, C.-W., Hu, D., Lian, B. Q., Kleffel, S., Yang, Y., Neiswender, J., Khorasani, A. J., Fang, R., Lezcano, C., Duncan, L. M., Scolyer, R. A., Thompson, J. F., Kakavand, H., Houvras, Y., Zon, L. I., Mihm, M. C., Kaiser, U. B., Schatton, T., Woda, B. A., Murphy, G. F., & Shi, Y. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Fudan University (CN)
- University of Massachusetts Chan Medical School (US)
- Ziopharm Oncology (United States) (US)
- Harvard University (US)
- The University of Sydney (AU)
- Corresponding author
- Shi, Yujiang G.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 150
- Issue
- 6
- Pages
- 1135-1146
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3770275
- OpenAlex
- W2029746613
- Cited by
- 789
- References
- 40
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 34 · 2023: 32 · 2022: 53 · 2021: 56 · 2020: 53 · 2019: 60 · 2018: 67 · 2017: 75 · 2016: 76 · 2015: 73 · 2014: 86 · 2013: 71 · 2012: 8
- FWCI
- 30.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ministry of Education of the People's Republic of China
- Fudan University
- National Institutes of Health (5P50CA093683-09)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- 5-hydroxymethylcytosine, melanoma, DNA methylation, TET enzymes, IDH2, TET2, epigenetic cancer therapy, tumor suppressor, prognostic factors, melanoma progression
- MeSH terms
- Cytosine, DNA-Binding Proteins, Humans, Isocitrate Dehydrogenase, Melanocytes, Melanoma, Nevus, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Epigenesis, Genetic, 5-Methylcytosine, Dioxygenases, Genome-Wide Association Study
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