title: Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.
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.
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christine Guo
authors.initials: CG
authors.lastname: Lian
authors.forename: Yufei
authors.initials: Y
authors.lastname: Xu
authors.forename: Craig
authors.initials: C
authors.lastname: Ceol
authors.forename: Feizhen
authors.initials: F
authors.lastname: Wu
authors.forename: Allison
authors.initials: A
authors.lastname: Larson
authors.forename: Karen
authors.initials: K
authors.lastname: Dresser
authors.forename: Wenqi
authors.initials: W
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.forename: Yeguang
authors.initials: Y
authors.lastname: Hu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.forename: Chung-Wei
authors.initials: CW
authors.lastname: Lee
authors.forename: Di
authors.initials: D
authors.lastname: Hu
authors.forename: Bill Q
authors.initials: BQ
authors.lastname: Lian
authors.forename: Sonja
authors.initials: S
authors.lastname: Kleffel
authors.forename: Yijun
authors.initials: Y
authors.lastname: Yang
authors.forename: James
authors.initials: J
authors.lastname: Neiswender
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Khorasani
authors.forename: Rui
authors.initials: R
authors.lastname: Fang
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Duncan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Hojabr
authors.initials: H
authors.lastname: Kakavand
authors.forename: Yariv
authors.initials: Y
authors.lastname: Houvras
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.forename: Ursula B
authors.initials: UB
authors.lastname: Kaiser
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Woda
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Yujiang G
authors.initials: YG
authors.lastname: Shi
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D009506:Nevus / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human