title: 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.
authors.affiliation: Department of Periodontics and Oral Medicine, Medical School, University of Michigan, Ann Arbor, MI 48109-1078, USA.
authors.forename: R
authors.initials: R
authors.lastname: Banerjee
authors.forename: R-S
authors.initials: RS
authors.lastname: Mani
authors.forename: N
authors.initials: N
authors.lastname: Russo
authors.forename: C S
authors.initials: CS
authors.lastname: Scanlon
authors.forename: A
authors.initials: A
authors.lastname: Tsodikov
authors.forename: X
authors.initials: X
authors.lastname: Jing
authors.forename: Q
authors.initials: Q
authors.lastname: Cao
authors.forename: N
authors.initials: N
authors.lastname: Palanisamy
authors.forename: T
authors.initials: T
authors.lastname: Metwally
authors.forename: R C
authors.initials: RC
authors.lastname: Inglehart
authors.forename: S
authors.initials: S
authors.lastname: Tomlins
authors.forename: C
authors.initials: C
authors.lastname: Bradford
authors.forename: T
authors.initials: T
authors.lastname: Carey
authors.forename: G
authors.initials: G
authors.lastname: Wolf
authors.forename: S
authors.initials: S
authors.lastname: Kalyana-Sundaram
authors.forename: A M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: S
authors.initials: S
authors.lastname: Varambally
authors.forename: N J
authors.initials: NJ
authors.lastname: D'Silva
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D020690:GTPase-Activating Proteins; D006657:Histones; C534072:MIRN101 microRNA, human; D035683:MicroRNAs; C484658:RAP1GAP protein, human; D014157:Transcription Factors; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D008239:Lysine