GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification

被引：121

作者：

Chung, Vin Yee ^{[1
]}

Tan, Tuan Zea ^{[1
]}

Tan, Ming ^{[1
]}

Wong, Meng Kang ^{[1
]}

Kuay, Kuee Theng ^{[1
]}

Yang, Zhe ^{[1
]}

Ye, Jieru ^{[1
]}

Muller, Julius ^{[2
]}

Koh, Cheryl M. ^{[2
]}

Guccione, Ernesto ^{[2
]}

Thiery, Jean Paul ^{[1
,2
,3
]}

Huang, Ruby Yun-Ju ^{[1
,4
,5
]}

机构：

[1] Natl Univ Singapore, Ctr Translat Med, Canc Sci Inst Singapore, 14 Med Dr,12-01, Singapore 117599, Singapore

[2] ASTAR, Inst Mol & Cell Biol, 61 Biopolis Dr, Singapore 13867, Singapore

[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, MD 7,8 Med Dr, Singapore 117596, Singapore

[4] Natl Univ Singapore Hosp, Dept Obstet & Gynaecol, 5 Lower Kent Ridge Rd, Singapore 119074, Singapore

[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, 14 Med Dr,MD6,14-02T, Singapore 117599, Singapore

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

新加坡国家研究基金会;

关键词：

GRAINYHEAD-LIKE; 2; MESENCHYMAL TRANSITION EMT; FEEDBACK LOOP; DNA METHYLATION; GENE SIGNATURE; GRHL2; SUPPRESSION; EXPRESSION; REVEALS; FAMILY;

D O I：

10.1038/srep19943

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Epithelial-mesenchymal transition (EMT), a biological process by which polarized epithelial cells convert into a mesenchymal phenotype, has been implicated to contribute to the molecular heterogeneity of epithelial ovarian cancer (EOC). Here we report that a transcription factor-Grainyhead-like 2 (GRHL2) maintains the epithelial phenotype. EOC tumours with lower GRHL2 levels are associated with the Mes/Mesenchymal molecular subtype and a poorer overall survival. shRNA-mediated knockdown of GRHL2 in EOC cells with an epithelial phenotype results in EMT changes, with increased cell migration, invasion and motility. By ChIP-sequencing and gene expression microarray, microRNA-200b/a is identified as the direct transcriptional target of GRHL2 and regulates the epithelial status of EOC through ZEB1 and E-cadherin. Our study demonstrates that loss of GRHL2 increases the levels of histone mark H3K27me3 on promoters and GRHL2-binding sites at miR-200b/a and E-cadherin genes. These findings support GRHL2 as a pivotal gatekeeper of EMT in EOC via miR-200-ZEB1.

引用

页数：15

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