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  • Original Article
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The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma

Abstract

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.

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Acknowledgements

We thank Dr T Giardano for tissue, and Dr Khalid Suleman and Vineeta Sharma for technical assistance for the FISH and methylation studies, respectively. R-SM is the recipient of StewartRahr–PCF Young Investigator Award from the Prostate Cancer Foundation. This work was supported by NIDCR DE16920-01, DE018512-01 grants and funding from University of Michigan Head and Neck Specialized Program of Research Excellence (SPORE) (NJD). This research was made possible, in part, by the use of the Cancer Center Flow Cytometry Core, which was supported (in part) by the National Institutes of Health through the University of Michigan's Cancer Center Support Grant (5 P30 CA46592).

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Correspondence to N J D'Silva.

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Banerjee, R., Mani, RS., Russo, N. et al. The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma. Oncogene 30, 4339–4349 (2011). https://doi.org/10.1038/onc.2011.141

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