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Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. 2012
Christine Guo Lian, and
Yufei Xu, and
Craig Ceol, and
Feizhen Wu, and
Allison Larson, and
Karen Dresser, and
Wenqi Xu, and
Li Tan, and
Yeguang Hu, and
Qian Zhan, and
Chung-Wei Lee, and
Di Hu, and
Bill Q Lian, and
Sonja Kleffel, and
Yijun Yang, and
James Neiswender, and
Abraham J Khorasani, and
Rui Fang, and
Cecilia Lezcano, and
Lyn M Duncan, and
Richard A Scolyer, and
John F Thompson, and
Hojabr Kakavand, and
Yariv Houvras, and
Leonard I Zon, and
Martin C Mihm, and
Ursula B Kaiser, and
Tobias Schatton, and
Bruce A Woda, and
George F Murphy, and
Yujiang G Shi
Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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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