Loss of 5-Hydroxymethylcytosine Is an Epigenetic Hallmark of Melanoma

被引：643

作者：

Lian, Christine Guo ^{[1
,2
]}

Xu, Yufei ^{[2
]}

Ceol, Craig ^{[3
,6
]}

Wu, Feizhen ^{[9
]}

Larson, Allison ^{[5
]}

Dresser, Karen ^{[7
]}

Xu, Wenqi ^{[9
]}

Tan, Li ^{[9
]}

Hu, Yeguang ^{[2
]}

Zhan, Qian ^{[1
]}

Lee, Chung-wei ^{[1
]}

Hu, Di ^{[2
]}

Lian, Bill Q. ^{[2
,8
]}

Kleffel, Sonja ^{[5
]}

Yang, Yijun ^{[10
]}

Neiswender, James ^{[6
]}

Khorasani, Abraham J. ^{[2
]}

Fang, Rui ^{[2
]}

Lezcano, Cecilia ^{[1
]}

Duncan, Lyn M. ^{[4
]}

Scolyer, Richard A. ^{[11
,12
]}

Thompson, John F. ^{[11
,12
]}

Kakavand, Hojabr ^{[11
,12
]}

Houvras, Yariv ^{[3
,13
,14
,15
]}

Zon, Leonard I. ^{[3
]}

Mihm, Martin C., Jr. ^{[5
]}

Kaiser, Ursula B. ^{[2
]}

Schatton, Tobias ^{[5
]}

Woda, Bruce A. ^{[7
]}

Murphy, George F. ^{[1
]}

Shi, Yujiang G. ^{[2
,9
]}

机构：

[1] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Dermatopathol,Dept Pathol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens,Dept Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Howard Hughes Med Inst,Harvard Stem Cell Inst, Stem Cell Program & Hematol Oncol,Childrens Hosp, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Dermatopathol,Dept Pathol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA

[6] Univ Massachusetts, Dept Canc Biol, Worcester, MA 01605 USA

[7] Univ Massachusetts, Dept Pathol, Worcester, MA 01605 USA

[8] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA

[9] Fudan Univ, Inst Biomed Sci, Lab Epigenet, Shanghai 200032, Peoples R China

[10] ZIOPHARM Oncol Inc, Charlestown, MA 02129 USA

[11] Univ Sydney, Melanoma Inst Australia, Royal Prince Alfred Hosp, Sydney, NSW 2006, Australia

[12] Univ Sydney, Sydney Med Sch, Sydney, NSW 2006, Australia

[13] Weill Cornell Med Coll, Dept Surg, New York, NY 10065 USA

[14] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[15] New York Presbyterian Hosp, New York, NY 10065 USA

来源：

CELL | 2012年 / 150卷 / 06期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION; DNA-METHYLATION; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; CELL-LINES; 5-METHYLCYTOSINE; MUTATIONS; TET1; DIFFERENTIATION; IDENTIFICATION; PROGRESSION;

D O I：

10.1016/j.cell.2012.07.033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1135 / 1146

页数：12

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