FAT1, a direct transcriptional target of E2F1, suppresses cell proliferation, migration and invasion in esophageal squamous cell carcinoma

Yu Wang; Guangchao Wang; Yunping Ma; Jinglei Teng; Yan Wang; Yongping Cui; Yan Dong; Shujuan Shao; Qimin Zhan; Xuefeng Liu

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FAT1, a direct transcriptional target of E2F1, suppresses cell proliferation, migration and invasion in esophageal squamous cell carcinoma

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Objective: Growing evidence indicates that FAT atypical cadherin 1(FAT1) has aberrant genetic alterations and exhibits potential tumor suppressive function in esophageal squamous cell carcinoma(ESCC). However, the role of FAT1 in ESCC tumorigenesis remains not well elucidated. The aim of this study was to further investigate genetic alterations and biological functions of FAT1, as well as to explore its transcriptional regulation and downstream targets in ESCC.Methods: The mutations of FAT1 in ESCC were achieved by analyzing a combined study from seven published genomic data, while the copy number variants of FAT1 were obtained from an analysis of our previous data as well as of The Cancer Genome Atlas(TCGA) and Cancer Cell Line Encyclopedia(CCLE) databases using the cBioPortal. The transcriptional regulation of FAT1 expression was investigated by chromatin immunoprecipitation(ChIP) and the luciferase reporter assays. In-cell western, Western blot and reverse transcription-quantitative polymerase chain reaction(RT-qPCR) were used to assess the indicated gene expression. In addition, colony formation and Transwell migration/invasion assays were employed to test cell proliferation, migration and invasion.Finally, RNA sequencing was used to study the transcriptomes.Results: FAT1 was frequently mutated in ESCC and was deleted in multiple cancers. Furthermore, the transcription factor E2 F1 occupied the promoter region of FAT1, and depletion of E2 F1 led to a decrease in transcription activity and mRNA levels of FAT1. Moreover, we found that knockdown of FAT1 promoted KYSE30 and KYSE150 cell proliferation, migration and invasion;while overexpression of FAT1 inhibited KYSE30 and KYSE410 cell proliferation, migration and invasion. In addition, knockdown of FAT1 led to enrichment of the mitogen-activated protein kinase(MAPK) signaling pathway and cell adhesion process.Conclusions: Our data provided evidence for the tumor suppressive function of FAT1 in ESCC cells and elucidated the transcriptional regulation of FAT1 by E2 F1, which may facilitate the understanding of molecular mechanisms of the progression of ESCC.

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《中国癌症研究：英文版》 |2019年第4期|609-619|共11页
作者
Yu Wang; Guangchao Wang; Yunping Ma; Jinglei Teng; Yan Wang; Yongping Cui; Yan Dong; Shujuan Shao; Qimin Zhan; Xuefeng Liu;
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作者单位

Institute of Cancer Stem Cell;

Dalian Medical University;

Dalian 116044;

China;

State Key Laboratory of Molecular Oncology;

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital;

Chinese Academy of Medical Sciences and Peking Union Medical College;

Beijing 100021;

China;

Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing);

Laboratory of Molecular Oncology;

Peking University Cancer Hospital&Institute;

Beijing 100142;

China;

Shenzhen Peking University-The Hong Kong University of Science and Technology(PKU-HKUST)Medical Center;

Peking University Shenzhen Hospital;

Shenzhen 518036;

China;

College of Stomatology;

Dalian Medical University;

Dalian116044;

China;

Key Laboratory of Proteomics;

Dalian Medical University;

Dalian 116044;

China;

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原文格式 PDF
正文语种 chi
中图分类食管肿瘤;
关键词
E2F1; ESCC; FAT1; tumor; suppressor;

FAT1, a direct transcriptional target of E2F1, suppresses cell proliferation, migration and invasion in esophageal squamous cell carcinoma

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