Department of Periodontics and Oral Medicine, Medical School, University of Michigan, Ann Arbor, MI 48109-1078, USA.
Oncogene. 2011 Oct 20;30(42):4339-49. doi: 10.1038/onc.2011.141. Epub 2011 May 2.
Rap1GAP is a critical tumor suppressor gene that is downregulated in multiple aggressive cancers, such as head and neck squamous cell carcinoma, melanoma and pancreatic cancer. However, the mechanistic basis of rap1GAP downregulation in cancers is poorly understood. By employing an integrative approach, we demonstrate polycomb-mediated repression of rap1GAP that involves Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase in head and neck cancers. We further demonstrate that the loss of miR-101 expression correlates with EZH2 upregulation, and the concomitant downregulation of rap1GAP in head and neck cancers. EZH2 represses rap1GAP by facilitating the trimethylation of histone 3 at lysine 27, a mark of gene repression, and also hypermethylation of rap1GAP promoter. These results provide a conceptual framework involving a microRNA-oncogene-tumor suppressor axis to understand head and neck cancer progression.
Rap1GAP 是一个关键的肿瘤抑制基因，在多种侵袭性癌症中下调，如头颈部鳞状细胞癌、黑色素瘤和胰腺癌。然而，Rap1GAP 在癌症中下调的机制基础还知之甚少。通过采用综合方法，我们证明了多梳介导的 Rap1GAP 抑制，涉及头颈部癌症中的 Enhancer of Zeste Homolog 2（EZH2），一种组蛋白甲基转移酶。我们进一步证明，miR-101 表达的丧失与 EZH2 的上调相关，以及头颈部癌症中 Rap1GAP 的下调。EZH2 通过促进组蛋白 3 赖氨酸 27 的三甲基化来抑制 Rap1GAP，这是基因抑制的标志，同时 Rap1GAP 启动子的过度甲基化。这些结果提供了一个概念框架，涉及 microRNA-oncogene-肿瘤抑制轴，以理解头颈部癌症的进展。
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