Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2
Abstract Background Abnormal expression of numerous long non-coding RNAs (lncRNAs) has been reported in esophageal squamous cell carcinoma (ESCC) recently, but the great majority of their roles and mechanisms remain largely unclear. We aim to identify the critical ESCC-associated lncRNAs and elucida...
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doaj-d5d8e0e9e9ac4faf911bdbe927b3a3ae2020-11-24T20:44:14ZengBMCMolecular Cancer1476-45982017-08-0116111310.1186/s12943-017-0715-7Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2Yuanyuan Wu0Liwen Hu1Yan Liang2Juan Li3Kai Wang4Xuedan Chen5Hui Meng6Xingying Guan7Kang Yang8Yun Bai9Department of Medical Genetics, College of Basic Medical Science, Third Military Medical UniversityDepartment of Cardiothoracic Surgery, Jinling Hospital, Medical school of Nanjing UniversityDepartment of Medical Genetics, College of Basic Medical Science, Third Military Medical UniversityDepartment of Medical Genetics, College of Basic Medical Science, Third Military Medical UniversityDepartment of Medical Genetics, College of Basic Medical Science, Third Military Medical UniversityDepartment of Medical Genetics, College of Basic Medical Science, Third Military Medical UniversityDepartment of clinical laboratory, Wuhan General Hospital of PLADepartment of Medical Genetics, College of Basic Medical Science, Third Military Medical UniversityDepartment of Cardiothoracic Surgery, Southwest Hospital, Third Military Medical UniversityDepartment of Medical Genetics, College of Basic Medical Science, Third Military Medical UniversityAbstract Background Abnormal expression of numerous long non-coding RNAs (lncRNAs) has been reported in esophageal squamous cell carcinoma (ESCC) recently, but the great majority of their roles and mechanisms remain largely unclear. We aim to identify the critical ESCC-associated lncRNAs and elucidate the functions and mechanisms in detail. Methods Microarrays were used to analyze the differentially expressed lncRNAs in ESCC tissues. qRT-PCR was used to verify the result of microarrays. The effects of the most up-regulated lncRNA, cancer susceptibility candidate 9(CASC9), on cell growth, proliferation and cell cycle were investigated by in vivo and in vitro assays. Microarrays and recovery tests were used to discover the regulatory targets of CASC9. RNA FISH and subcellular fractionation assays were used to detect the subcellular location of CASC9. Finally, the mechanism of CASC9 regulating PDCD4 was explored by RIP, RNA-protein pull down and ChIP assays. Results ESCC tissue microarrays showed that CASC9 was the most up-regulated lncRNA. qRT-PCR analysis indicated that CASC9 expression was positively associated with tumor size and TNM stage, and predicted poor overall survival of ESCC patients. Knockdown of CASC9 inhibited ESCC cell growth in vitro and tumorigenesis in nude mice. Furthermore interfering CASC9 decreased cell proliferation and blocked cell cycle G1/S transition. CASC9-associated microarrays indicated that PDCD4 might be the target of CASC9. Consistent with this, PDCD4 expression was negatively associated with CASC9 expression in ESCC tissues and predicted good prognosis. Manipulating CASC9 expression in ESCC cells altered both PDCD4 mRNA and protein levels and cell cycle arrest caused by CASC9 knockdown could be rescued by suppressing PDCD4 expression. CASC9 located both in the nucleus and cytoplasm. Mechanistically, enhancer of zeste homolog2 (EZH2) could bind to both CASC9 and PDCD4 promoter region. Interfering CASC9 reduced the enrichment of EZH2 and H3K27me3 in the PDCD4 promoter region. Conclusions Our study firstly demonstrates that lncRNA CASC9 functions as an oncogene by negatively regulating PDCD4 expression through recruiting EZH2 and subsequently altering H3K27me3 level. Our study implicates lncRNA CASC9 as a valuable biomarker for ESCC diagnosis and prognosis.http://link.springer.com/article/10.1186/s12943-017-0715-7lncRNAESCCCASC9PDCD4And EZH2 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yuanyuan Wu Liwen Hu Yan Liang Juan Li Kai Wang Xuedan Chen Hui Meng Xingying Guan Kang Yang Yun Bai |
spellingShingle |
Yuanyuan Wu Liwen Hu Yan Liang Juan Li Kai Wang Xuedan Chen Hui Meng Xingying Guan Kang Yang Yun Bai Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2 Molecular Cancer lncRNA ESCC CASC9 PDCD4 And EZH2 |
author_facet |
Yuanyuan Wu Liwen Hu Yan Liang Juan Li Kai Wang Xuedan Chen Hui Meng Xingying Guan Kang Yang Yun Bai |
author_sort |
Yuanyuan Wu |
title |
Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2 |
title_short |
Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2 |
title_full |
Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2 |
title_fullStr |
Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2 |
title_full_unstemmed |
Up-regulation of lncRNA CASC9 promotes esophageal squamous cell carcinoma growth by negatively regulating PDCD4 expression through EZH2 |
title_sort |
up-regulation of lncrna casc9 promotes esophageal squamous cell carcinoma growth by negatively regulating pdcd4 expression through ezh2 |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2017-08-01 |
description |
Abstract Background Abnormal expression of numerous long non-coding RNAs (lncRNAs) has been reported in esophageal squamous cell carcinoma (ESCC) recently, but the great majority of their roles and mechanisms remain largely unclear. We aim to identify the critical ESCC-associated lncRNAs and elucidate the functions and mechanisms in detail. Methods Microarrays were used to analyze the differentially expressed lncRNAs in ESCC tissues. qRT-PCR was used to verify the result of microarrays. The effects of the most up-regulated lncRNA, cancer susceptibility candidate 9(CASC9), on cell growth, proliferation and cell cycle were investigated by in vivo and in vitro assays. Microarrays and recovery tests were used to discover the regulatory targets of CASC9. RNA FISH and subcellular fractionation assays were used to detect the subcellular location of CASC9. Finally, the mechanism of CASC9 regulating PDCD4 was explored by RIP, RNA-protein pull down and ChIP assays. Results ESCC tissue microarrays showed that CASC9 was the most up-regulated lncRNA. qRT-PCR analysis indicated that CASC9 expression was positively associated with tumor size and TNM stage, and predicted poor overall survival of ESCC patients. Knockdown of CASC9 inhibited ESCC cell growth in vitro and tumorigenesis in nude mice. Furthermore interfering CASC9 decreased cell proliferation and blocked cell cycle G1/S transition. CASC9-associated microarrays indicated that PDCD4 might be the target of CASC9. Consistent with this, PDCD4 expression was negatively associated with CASC9 expression in ESCC tissues and predicted good prognosis. Manipulating CASC9 expression in ESCC cells altered both PDCD4 mRNA and protein levels and cell cycle arrest caused by CASC9 knockdown could be rescued by suppressing PDCD4 expression. CASC9 located both in the nucleus and cytoplasm. Mechanistically, enhancer of zeste homolog2 (EZH2) could bind to both CASC9 and PDCD4 promoter region. Interfering CASC9 reduced the enrichment of EZH2 and H3K27me3 in the PDCD4 promoter region. Conclusions Our study firstly demonstrates that lncRNA CASC9 functions as an oncogene by negatively regulating PDCD4 expression through recruiting EZH2 and subsequently altering H3K27me3 level. Our study implicates lncRNA CASC9 as a valuable biomarker for ESCC diagnosis and prognosis. |
topic |
lncRNA ESCC CASC9 PDCD4 And EZH2 |
url |
http://link.springer.com/article/10.1186/s12943-017-0715-7 |
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