Dataset Information

Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer.

ABSTRACT: Long noncoding RNAs (lncRNAs) have received increased attention as a new class of functional regulators involved in human carcinogenesis. HOXA cluster antisense RNA 2 (HOXA-AS2) is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster that regulates gene expression at a transcription level. HOXA-AS2 is previously found to be overexpressed in gastric cancer (GC) and promotes GC cells proliferation. However, its potential role and molecular mechanism in colorectal cancer (CRC) are not known. Here, we identified that HOXA-AS2 is significantly upregulated in CRC tissue. In addition, increased HOXA-AS2 expression is associated with a larger tumor size and an advanced pathological stage in CRC patients. HOXA-AS2 knockdown significantly suppressed proliferation by blocking the G1/S transition and caused apoptosis of CRC cells in vitro and in vivo. The mechanistic investigations showed that HOXA-AS2 could interact with EZH2 (enhancer of zeste homolog 2), LSD1 (lysine specific demethylase 1) and recruit them to p21 (CDKN1A), KLF2 promoter regions to repress their transcription. Furthermore, the rescue experiments demonstrated that HOXA-AS2 oncogenic function is partly through regulating p21. In conclusion, our data suggest that HOXA-AS2 may function as an oncogene by modulating the multiple genes expression involved in CRC proliferation, and also provides a potential target for CRC therapy.

SUBMITTER: Ding J

PROVIDER: S-EPMC5294247 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer.

Ding J J Xie M M Lian Y Y Zhu Y Y Peng P P Wang J J Wang L L Wang K K

Oncogenesis 20170123 1

Long noncoding RNAs (lncRNAs) have received increased attention as a new class of functional regulators involved in human carcinogenesis. HOXA cluster antisense RNA 2 (HOXA-AS2) is a 1048-bp lncRNA located between the HOXA3 and HOXA4 genes in the HOXA cluster that regulates gene expression at a transcription level. HOXA-AS2 is previously found to be overexpressed in gastric cancer (GC) and promotes GC cells proliferation. However, its potential role and molecular mechanism in colorectal cancer ( ...[more]

PMID: 28112720

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Project description:To explore the function and mechanism of lncRNA HOXA-AS2 in cancer-associated fibroblasts (CAFs)-derived exosomes in gallbladder cancer metastasis, and provide new research targets for the treatment of gallbladder cancer. At the same time, in order to clarify the early predictive value of lncRNA HOXA-AS2 for gallbladder cancer metastasis, and to provide a theoretical basis for clinical individualized treatment of gallbladder cancer. Methods. In our previous work, we used TCGA database analysis to find that lncRNA HOXA-AS2 was highly expressed in gallbladder cancer tissues compared with normal tissues. In this study, the expression levels of HOXA-AS2 in gallbladder cancer cell lines and control cells were first verified by QPCR and Western blot methods. Then, lentiviral tools were used to construct knockdown vectors (RNAi#1, RNAi#2) and negative control vectors targeting two different sites of HOXA-AS2, and the vectors were transfected into NOZ and OCUG-1 cells, respectively. Real-time PCR was used to detect knockdown efficiency. Then, the effects of silencing HOXA-AS2 on the proliferation, cell viability, cell migration, and invasion ability of gallbladder cancer cells were detected by MTT, plate cloning assay, Transwell migration chamber assay, and Transwell invasion chamber assay. Finally, the interaction between HOXA-AS2 and miR-6867 and the 3′UTR of YAP1 protein was detected by luciferase reporter gene. The results showed that the expression level of HOXA-AS2 in gallbladder cancer cell lines was higher than that in control cells. The expression of HOXA-AS2 in gallbladder carcinoma tissues was significantly higher than that in adjacent tissues (p < 0.05). After successful knockout of HOXA-AS2 by lentiviral transfection, the expression of HOXA-AS2 in gallbladder cancer cell lines was significantly decreased. Through cell proliferation and plate clone detection, it was found that silencing HOXA-AS2 inhibited cell proliferation and invasion. Through software prediction and fluorescein reporter gene detection, it was found that HOXA-AS2 has a binding site with miR-6867, and the two are negatively correlated, that is, the expression of miR-6867 is enhanced after the expression of HOXA-AS2 is downregulated. And the 3′UTR of YAP1 protein in the Hippo signaling pathway binds to miR-6867. Therefore, HOXA-AS2 may affect the expression of YAP1 protein by regulating miR-6867, thereby inhibiting the Hippo signaling pathway and promoting the proliferation and metastasis of gallbladder cancer cells. HOXA-AS2 is abnormally expressed in gallbladder cancer cells. HOXA-AS2 may promote the migration and invasion of gallbladder cancer cells by regulating the Hippo signaling pathway through miR-6867. HOXA-AS2 may serve as a potential diagnostic and therapeutic target for gallbladder cancer in clinic.

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.

Dataset Information

Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer.

Publications

Long noncoding RNA HOXA-AS2 represses P21 and KLF2 expression transcription by binding with EZH2, LSD1 in colorectal cancer.

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