Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation

被引：478

作者：

Kondo, Yutaka ^{[1
,2
]}

Shen, Lanlan ^{[1
]}

Cheng, Alfred S. ^{[3
]}

Ahmed, Saira ^{[1
]}

Boumber, Yanis ^{[1
]}

Charo, Chantale ^{[1
]}

Yamochi, Tadanori ^{[4
]}

Urano, Takeshi ^{[5
]}

Furukawa, Koichi ^{[5
]}

Kwabi-Addo, Bernard ^{[6
]}

Gold, David L. ^{[7
]}

Sekido, Yoshitaka ^{[2
]}

Huang, Tim Hui-Ming ^{[3
]}

Issa, Jean-Pierre J. ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[2] Aichi Canc Ctr, Res Inst, Div Mol Oncol, Chikusa Ku, Nagoya, Aichi 4648681, Japan

[3] Ohio State Univ, Human Canc Genet Program, Dept Mol Virol Immunol & Med Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA

[5] Nagoya Univ, Grad Sch Med, Dept Biochem 2, Showa Ku, Nagoya, Aichi 4668550, Japan

[6] Baylor Coll Med & Michael E DeBakey, Dept Pathol, Dept Vet Affairs Med Ctr, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Biostat & Appl Math, Houston, TX 77030 USA

来源：

NATURE GENETICS | 2008年 / 40卷 / 06期

关键词：

D O I：

10.1038/ng.159

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation.

引用

页码：741 / 750

页数：10

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