Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma

Cell. 2012 Sep 14;150(6):1135-46. doi: 10.1016/j.cell.2012.07.033.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • Cytosine / analogs & derivatives*
  • Cytosine / metabolism
  • DNA-Binding Proteins / genetics
  • Epigenesis, Genetic*
  • Gene Expression Regulation, Neoplastic*
  • Genome-Wide Association Study
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Melanocytes / metabolism
  • Melanoma / genetics*
  • Melanoma / pathology
  • Nevus / genetics*
  • Nevus / pathology
  • Proto-Oncogene Proteins / genetics

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • TET2 protein, human
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Cytosine
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human

Associated data

  • GEO/GSE38231