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转发:Nature :一个新的肿瘤抑制机制

发表时间:2010-12-24  |  阅读次数:24次  |  字体大小 [ ]

组蛋白变体mH2A被发现在很多黑素瘤中表达水平降低。mH2A的失去通过CDK8的转录上调促进肿瘤生长和转移,而CDK8是一个已知的致癌基因。因此,这项研究揭示了一个由染色质修饰所施加的新的肿瘤抑制机制。

(转发自生物谷Bioon.com)

原文出处:

Nature   doi:10.1038/nature09590

The histone variant macroH2A suppresses melanoma progression through regulation of CDK8

Avnish Kapoor,Matthew S. Goldberg,Lara K. Cumberland,Kajan Ratnakumar,Miguel F. Segura,Patrick O. Emanuel,Silvia Menendez,Chiara Vardabasso,Gary LeRoy,Claudia I. Vidal,David Polsky,Iman Osman,Benjamin A. Garcia,Eva Hernando& Emily Bernstein

Cancer is a disease consisting of both genetic and epigenetic changes. Although increasing evidence demonstrates that tumour progression entails chromatin-mediated changes such as DNA methylation, the role of histone variants in cancer initiation and progression currently remains unclear. Histone variants replace conventional histones within the nucleosome and confer unique biological functions to chromatin1, 2, 3. Here we report that the histone variant macroH2A (mH2A) suppresses tumour progression of malignant melanoma. Loss of mH2A isoforms, histone variants generally associated with condensed chromatin and fine-tuning of developmental gene expression programs1, 4, 5, 6, is positively correlated with increasing malignant phenotype of melanoma cells in culture and human tissue samples. Knockdown of mH2A isoforms in melanoma cells of low malignancy results in significantly increased proliferation and migration in vitro and growth and metastasis in vivo. Restored expression of mH2A isoforms rescues these malignant phenotypes in vitro and in vivo. We demonstrate that the tumour-promoting function of mH2A loss is mediated, at least in part, through direct transcriptional upregulation of CDK8. Suppression of CDK8, a colorectal cancer oncogene7, 8, inhibits proliferation of melanoma cells, and knockdown of CDK8 in cells depleted of mH2A suppresses the proliferative advantage induced by mH2A loss. Moreover, a significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples. Taken together, our results demonstrate that mH2A is a critical component of chromatin that suppresses the development of malignant melanoma, a highly intractable cutaneous neoplasm.

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