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

被引：93

作者：

Banerjee, R.

Mani, R-S ^{[2
,3
]}

Russo, N.

Scanlon, C. S.

Tsodikov, A. ^{[4
]}

Jing, X. ^{[2
,3
]}

Cao, Q. ^{[3
]}

Palanisamy, N. ^{[2
,3
]}

Metwally, T.

Inglehart, R. C.

Tomlins, S. ^{[2
,3
]}

Bradford, C. ^{[5
]}

Carey, T. ^{[5
]}

Wolf, G. ^{[5
]}

Kalyana-Sundaram, S. ^{[2
,3
,6
]}

Chinnaiyan, A. M. ^{[2
,3
,7
]}

Varambally, S. ^{[2
,3
]}

D'Silva, N. J. ^{[1
,2
,3
]}

机构：

[1] Univ Michigan, Sch Dent, Sch Med, Dept Periodont & Oral Med, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Sch Med, Dept Biostat, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Sch Med, Dept Otolaryngol, Ann Arbor, MI 48109 USA

[6] Bharathidasan Univ, Dept Environm Biotechnol, Tiruchirappalli, Tamil Nadu, India

[7] Univ Michigan, Sch Med, Dept Urol, Ann Arbor, MI 48109 USA

来源：

ONCOGENE | 2011年 / 30卷 / 42期

基金：

美国国家卫生研究院;

关键词：

miR-101; EZH2; rap1GAP; rap1; promoter hypermethylation; GROUP PROTEIN EZH2; HISTONE METHYLTRANSFERASE; DOWN-REGULATION; E-CADHERIN; SOMATIC MUTATIONS; MOLECULAR-BIOLOGY; PROMOTES INVASION; HIGH EXPRESSION; NECK-CANCER; POLYCOMB;

D O I：

10.1038/onc.2011.141

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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. Oncogene (2011) 30, 4339-4349; doi: 10.1038/onc.2011.141; published online 2 May 2011

引用

页码：4339 / 4349

页数：11

共 46 条

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