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Long non-coding RNA LINC01133 represses KLF2, P21 and E-cadherin transcription through binding with EZH2, LSD1 in non small cell lung cancer.

ABSTRACT: Long non-coding RNAs are emerging as crucial regulators and prognostic markers in multiple cancers including non small cell lung cancer (NSCLC). In this study, we screened LINCO1133 as a new candidate lncRNA which promotes NSCLC development and progression, in two independent datasets (GSE18842 and GSE19804) from the Gene Expression Omnibus (GEO). LINC01133 is previously found to be over-expressed in lung squamous cell cancer (LSCC) and knockdown its expression inhibits LSCC cells invasion. However, its' molecular mechanism and downstream targets involving in regulation of cancer cells phenotype is not known. Here, we found that LINC01133 expression is up-regulated in NSCLC tissues, and its' over-expression is associated with patients poor prognosis and short survival time. LINC01133 knockdown decreased NSCLC cells proliferation, migration, invasion and induced cell cycle G1/S phase arrest and cell apoptosis. Mechanistic investigations showed that LINC01133 could interact with EZH2, LSD1 and recruit them to KLF2, P21 or E-cadherin promoter regions to repress their transcription. Furthermore, rescue experiments demonstrated that LINC01133 oncogenic function is partly through regulating KLF2. Lastly, we found that there was negative correlation between LINC01133 and KLF2, P21 or E-cadherin in NSCLC. Overall, our findings illuminate how LINC01133 over-expression confers an oncogenic function in NSCLC that may offer a novel therapy target in this disease.

SUBMITTER: Zang C

PROVIDER: S-EPMC4905504 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough the prognosis of gastric cancer patients have a favorable progression, there are some patients with unusual patterns of locoregional and systemic recurrence. Therefore, a better understanding of early molecular events of the disease is needed. Current evidences demonstrate that long noncoding RNAs (lncRNAs) may be an important class of functional regulators involved in human gastric cancers development. Our previous studies suggest that HOTAIR contributes to gastric cancer development, and the overexpression of HOTAIR predicts a poor prognosis. In this study, we investigated the characteristic of the LncRNA FEZF1-AS1 in gastric cancer.MethodsQRT-PCR was used to detect the expression of FEZF1-AS1 in gastric cancer tissues and cells. MTT assays, clonogenic survival assays and nude mouse xenograft model were used to examine the tumorigenesis function of FEZF1-AS1 in vitro and in vivo. Bioinformatics analysis were used to select downstream target genes of FEZF1-AS1. Cell cycle analysis, ChIP, RIP,RNA Pulldown assays were examined to dissect molecular mechanisms.ResultsIn this study, we reported that FEZF1-AS1, a 2564 bp RNA, was overexpressed in gastric cancer, and upregulated FEZF1-AS1 expression indicated larger tumor size and higher clinical stage; additional higher expression of FEZF1-AS1 predicted poor prognosis. Further experiments revealed that knockdown FEZF1-AS1 significantly inhibited gastric cancer cells proliferation by inducing G1 arrest and apoptosis, whereas endogenous expression FEZF1-AS1 promoted cell growth. Additionally, RIP assay and RNA-pulldown assay evidenced that FEZF1-AS1 could epigenetically repress the expression of P21 via binding with LSD1, the first discovered demethylase. ChIP assays demonstrated that LSD1 could directly bind to the promoter of P21, inducing H3K4me2 demethylation.ConclusionIn summary, these data demonstrated that FEZF1-AS1 could act as an "oncogene" for gastric cancer partly through suppressing P21 expression; FEZF1-AS1 may be served as a candidate prognostic biomarker and target for new therapies of gastric cancer patients.

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Long non-coding RNA LINC01133 represses KLF2, P21 and E-cadherin transcription through binding with EZH2, LSD1 in non small cell lung cancer.

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