Home LiteratureArticle Details
PMID: 22980977 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.

Cell ·Vol. 150 ·No. 6 ·2012-09-14 ·Pages 1135-46

Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, Hu Y, Zhan Q, Lee CW, Hu D, Lian BQ, Kleffel S, Yang Y, Neiswender J, Khorasani AJ, Fang R, Lezcano C, Duncan LM, Scolyer RA, Thompson JF, Kakavand H, Houvras Y, Zon LI, Mihm MC, Kaiser UB, Schatton T, Woda BA, Murphy GF, Shi YG

Abstract

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.

MeSH Terms
5-Methylcytosine/analogs & derivatives Cytosine/analogs & derivatives,metabolism DNA-Binding Proteins/genetics Dioxygenases Epigenesis, Genetic Gene Expression Regulation, Neoplastic Genome-Wide Association Study Humans Isocitrate Dehydrogenase/genetics Melanocytes/metabolism Melanoma/genetics,pathology Nevus/genetics,pathology Proto-Oncogene Proteins/genetics
Chemicals
DNA-Binding Proteins Proto-Oncogene Proteins 5-hydroxymethylcytosine 5-Methylcytosine Cytosine IDH2, human Isocitrate Dehydrogenase Dioxygenases TET2 protein, human
Authors & Affiliations
31 authors, click to expand affiliations / ORCID
Lian Christine Guo
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Xu Yufei
Ceol Craig
Wu Feizhen
Larson Allison
Dresser Karen
Xu Wenqi
Tan Li
Hu Yeguang
Zhan Qian
Lee Chung-Wei
Hu Di
Lian Bill Q
Kleffel Sonja
Yang Yijun
Neiswender James
Khorasani Abraham J
Fang Rui
Lezcano Cecilia
Duncan Lyn M
Scolyer Richard A
Thompson John F
Kakavand Hojabr
Houvras Yariv
Zon Leonard I
Mihm Martin C
Kaiser Ursula B
Schatton Tobias
Woda Bruce A
Murphy George F
Shi Yujiang G
References (36)
36 references, click to expand
  1. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation.
    Genes Dev. 2011 Dec 1;25(23):2436-52 PMID: 22156206
  2. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.
    Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270-5 PMID: 21289278
  3. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells.
    Mol Cell. 2011 May 20;42(4):451-64 PMID: 21514197
  4. Novel genes associated with malignant melanoma but not benign melanocytic lesions.
    Clin Cancer Res. 2005 Oct 15;11(20):7234-42 PMID: 16243793
  5. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
    EMBO Rep. 2011 May;12(5):463-9 PMID: 21460794
  6. Screen for IDH1, IDH2, IDH3, D2HGDH and L2HGDH mutations in glioblastoma.
    PLoS One. 2011;6(5):e19868 PMID: 21625441
  7. Recent trends in cutaneous melanoma incidence among whites in the United States.
    J Natl Cancer Inst. 2001 May 2;93(9):678-83 PMID: 11333289
  8. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.
    Science. 2009 May 15;324(5929):930-5 PMID: 19372391
  9. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.
    Cancer Cell. 2011 Jan 18;19(1):17-30 PMID: 21251613
  10. Identification of tumor suppressors and oncogenes from genomic and epigenetic features in ovarian cancer.
    PLoS One. 2011;6(12):e28503 PMID: 22174824
  11. Identification of novel epigenetically modified genes in human melanoma via promoter methylation gene profiling.
    Pigment Cell Melanoma Res. 2008 Oct;21(5):545-58 PMID: 18627528
  12. Epidemiology of melanoma.
    Clin Exp Dermatol. 2000 Sep;25(6):459-63 PMID: 11044179
  13. Genome-wide profiling of DNA methylation reveals a class of normally methylated CpG island promoters.
    PLoS Genet. 2007 Oct;3(10):2023-36 PMID: 17967063
  14. Integrative genome comparison of primary and metastatic melanomas.
    PLoS One. 2010 May 24;5(5):e10770 PMID: 20520718
  15. Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA.
    Nucleic Acids Res. 2010 Oct;38(19):e181 PMID: 20685817
  16. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.
    Cancer Cell. 2010 Mar 16;17(3):225-34 PMID: 20171147
  17. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation.
    Oncogene. 2013 Jan 31;32(5):663-9 PMID: 22391558
  18. Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients.
    Oncogene. 2004 May 13;23(22):4014-22 PMID: 15064737
  19. The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis.
    BMC Med Genomics. 2008 Apr 28;1:13 PMID: 18442402
  20. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification.
    Nature. 2010 Aug 26;466(7310):1129-33 PMID: 20639862
  21. The gene expression signatures of melanoma progression.
    Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6092-7 PMID: 15833814
  22. TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine.
    Cell Res. 2010 Dec;20(12):1390-3 PMID: 21079648
  23. A systematic profile of DNA methylation in human cancer cell lines.
    Cancer Res. 2003 Mar 1;63(5):1114-21 PMID: 12615730
  24. Identification of cells initiating human melanomas.
    Nature. 2008 Jan 17;451(7176):345-9 PMID: 18202660
  25. TET family proteins and their role in stem cell differentiation and transformation.
    Cell Stem Cell. 2011 Sep 2;9(3):193-204 PMID: 21885017
  26. Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers.
    Oncotarget. 2011 Aug;2(8):627-37 PMID: 21896958
  27. Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine.
    Nat Biotechnol. 2011 Jan;29(1):68-72 PMID: 21151123
  28. Model-based analysis of ChIP-Seq (MACS).
    Genome Biol. 2008;9(9):R137 PMID: 18798982
  29. DNA-methylation profiling distinguishes malignant melanomas from benign nevi.
    Pigment Cell Melanoma Res. 2011 Apr;24(2):352-60 PMID: 21375697
  30. Cancer statistics, 2006.
    CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30 PMID: 16514137
  31. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.
    Nature. 2011 Mar 24;471(7339):513-7 PMID: 21430779
  32. Acquired mutations in TET2 are common in myelodysplastic syndromes.
    Nat Genet. 2009 Jul;41(7):838-42 PMID: 19483684
  33. CpG island methylation profiling in human melanoma cell lines.
    Melanoma Res. 2009 Jun;19(3):146-55 PMID: 19441164
  34. Mutation in TET2 in myeloid cancers.
    N Engl J Med. 2009 May 28;360(22):2289-301 PMID: 19474426
  35. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation.
    Nature. 2011 May 19;473(7347):398-402 PMID: 21460836
  36. IDH mutations in glioma and acute myeloid leukemia.
    Trends Mol Med. 2010 Sep;16(9):387-97 PMID: 20692206
Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.07.033
Published
2012-09-14
Pages
1135-46
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3770275
Subset
IM
Grants
NIGMS NIH HHS · GM078458 · United States
NCI NIH HHS · P50 CA093683 · United States
NIGMS NIH HHS · R01 GM078458 · United States
NIDDK NIH HHS · R01 DK077036 · United States
NCI NIH HHS · 5P50CA093683-09 · United States
NIGMS NIH HHS · F32 GM070690 · United States
Databases
GEO
GSE38231
Corrections
CommentIn
PMID: 23037450
External Links
PubMed source DOI: 10.1016/j.cell.2012.07.033 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2