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

Yutaka Kondo; Lanlan Shen; Alfred S. Cheng; Saira Ahmed; Yanis Boumber; Chantale Charo; Tadanori Yamochi; Takeshi Urano; Koichi Furukawa; Bernard Kwabi-Addo; David L. Gold; Yoshitaka Sekido; Tim Hui Ming Huang; Jean Pierre J. Issa

doi:10.1038/ng.159

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

Yutaka Kondo, Lanlan Shen, Alfred S. Cheng, Saira Ahmed, Yanis Boumber, Chantale Charo, Tadanori Yamochi, Takeshi Urano, Koichi Furukawa, Bernard Kwabi-Addo, David L. Gold, Yoshitaka Sekido, Tim Hui Ming Huang, Jean Pierre J. Issa

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Resumen

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.

Idioma original	English (US)
Páginas (desde-hasta)	741-750
Número de páginas	10
Publicación	Nature Genetics
Volumen	40
N.º	6
DOI	https://doi.org/10.1038/ng.159
Estado	Published - jun 2008
Publicado de forma externa	Sí

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Genetics

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title = "Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation",

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.",

author = "Yutaka Kondo and Lanlan Shen and Cheng, {Alfred S.} and Saira Ahmed and Yanis Boumber and Chantale Charo and Tadanori Yamochi and Takeshi Urano and Koichi Furukawa and Bernard Kwabi-Addo and Gold, {David L.} and Yoshitaka Sekido and Huang, {Tim Hui Ming} and Issa, {Jean Pierre J.}",

note = "Funding Information: This work was supported in part by US National Institutes of Health by grants P50CA100632, R33CA89837 and RO1CA098006 to J.-P.J.I. and grant P50CA058204 to B.K.-A. J.-P.J.I. is an American Cancer Society Clinical Research Professor supported by a generous gift from the F.M. Kirby Foundation. Y.K. was supported by an Odyssey Fellowship at the M.D. Anderson Cancer Center and the Cell Science Research Foundation. We especially thank Y. Guo and X. Chen for their technical assistance.",

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doi = "10.1038/ng.159",

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T1 - Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation

AU - Kondo, Yutaka

AU - Shen, Lanlan

AU - Cheng, Alfred S.

AU - Ahmed, Saira

AU - Boumber, Yanis

AU - Charo, Chantale

AU - Yamochi, Tadanori

AU - Urano, Takeshi

AU - Furukawa, Koichi

AU - Kwabi-Addo, Bernard

AU - Gold, David L.

AU - Sekido, Yoshitaka

AU - Huang, Tim Hui Ming

AU - Issa, Jean Pierre J.

N1 - Funding Information: This work was supported in part by US National Institutes of Health by grants P50CA100632, R33CA89837 and RO1CA098006 to J.-P.J.I. and grant P50CA058204 to B.K.-A. J.-P.J.I. is an American Cancer Society Clinical Research Professor supported by a generous gift from the F.M. Kirby Foundation. Y.K. was supported by an Odyssey Fellowship at the M.D. Anderson Cancer Center and the Cell Science Research Foundation. We especially thank Y. Guo and X. Chen for their technical assistance.

PY - 2008/6

Y1 - 2008/6

N2 - 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.

AB - 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.

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

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