Article abstract
Nature Genetics 40, 741 - 750 (2008)
Published online: 18 May 2008 | doi:10.1038/ng.159
Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation
Yutaka Kondo1,2,9, Lanlan Shen1,9, Alfred S Cheng3,8, Saira Ahmed1, Yanis Boumber1, Chantale Charo1, Tadanori Yamochi4, Takeshi Urano5, Koichi Furukawa5, Bernard Kwabi-Addo6, David L Gold7, Yoshitaka Sekido2, Tim Hui-Ming Huang3 & Jean-Pierre J Issa1
Abstract
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.
- Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
- Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
- Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, 420 West 12th Avenue, Columbus, Ohio 43210, USA.
- Department of Lymphoma/Myeloma, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
- Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan.
- Department of Pathology, Baylor College of Medicine and Michael E. DeBakey, Department of Veterans Affairs Medical Center, 1 Baylor Plaza, Houston, Texas 77030, USA.
- Department of Biostatistics and Applied Mathematics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
- Present address: Institute of Digestive Disease, Faculty of Medicine, Chinese University of Hong Kong, Li Ka Shing Medical Sciences Building, Prince of Wales Hospital, Shatin, N.T. Hong Kong SAR.
- These authors contributed equally to this work.
Correspondence to: Jean-Pierre J Issa1 e-mail: jpissa@mdanderson.org
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