Author/Authors :
Christine Guo Lian، نويسنده , , Yufei Xu، نويسنده , , Craig Ceol، نويسنده , , Feizhen Wu، نويسنده , , Allison Larson، نويسنده , , Karen Dresser، نويسنده , , Wenqi Xu، نويسنده , , Li Tan، نويسنده , , Yeguang Hu، نويسنده , , Qian Zhan، نويسنده , , Chung-wei Lee، نويسنده , , Di Hu، نويسنده , , Bill Q. Lian، نويسنده , , Sonja Kleffel، نويسنده , , Yijun Yang، نويسنده , , James Neiswender، نويسنده , , Abraham J. Khorasani، نويسنده , , Rui Fang، نويسنده , , Cecilia Lezcano، نويسنده , , Lyn M. Duncan، نويسنده , , et al.، نويسنده ,
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.
