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Long noncoding RNA PCAT6 inhibits colon cancer cell apoptosis by regulating anti-apoptotic protein ARC expression via EZH2.

ABSTRACT: Prostate cancer-associated ncRNA transcript 6 (PCAT6) is a long intergenic noncoding RNA that is involved in the progression of prostate and lung cancer, acting as a potential diagnostic and prognostic biomarker in nonsmall cell lung cancer. However, little is known about PCAT6 expression and its clinical significance in colon cancer. Here, we aimed to investigate the clinical significance of PCAT6 in colon cancer and its underlying mechanism. The expression of PCAT6 was analyzed in colon cancer tissues using public databases, and a series of in vitro and in vivo experiments was performed to investigate the biological functions of PCAT6 in colon cancer cells and the underlying mechanisms. Our results demonstrated that PCAT6 was upregulated in colon cancer tissues compared with that in noncancerous tissues, correlating with poorer clinical stages and a worse survival status. In vitro and in vivo experiments illustrated PCAT6 promoted cell growth and inhibited cell apoptosis in colon cancer. Mechanistically, PCAT6 enhanced the coenrichment of EZH2 and H3K4me3 at the apoptosis repressor with caspase recruitment domain (ARC) genomic region, promoting the transcriptional activity of ARC. Our data highlighted that PCAT6 acts as a key activator of ARC expression by forming a complex with EZH2, inhibiting cell apoptosis and contributing to colon cancer progression. These findings elucidated that PCAT6 may be a novel prognostic predictor and therapeutic target of colon cancer.

SUBMITTER: Huang W

PROVIDER: S-EPMC6343696 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Long noncoding RNA PCAT6 inhibits colon cancer cell apoptosis by regulating anti-apoptotic protein ARC expression via EZH2.

Huang Weimei W Su Geng G Huang Xiaoxian X Zou Angru A Wu Jingfang J Yang Yunchu Y Zhu Yaru Y Liang Shumei S Li Deyu D Ma Feng F Guo Linlang L

Cell cycle (Georgetown, Tex.) 20181230 1

Prostate cancer-associated ncRNA transcript 6 (PCAT6) is a long intergenic noncoding RNA that is involved in the progression of prostate and lung cancer, acting as a potential diagnostic and prognostic biomarker in nonsmall cell lung cancer. However, little is known about PCAT6 expression and its clinical significance in colon cancer. Here, we aimed to investigate the clinical significance of PCAT6 in colon cancer and its underlying mechanism. The expression of PCAT6 was analyzed in colon cancer ...[more]

PMID: 30569799

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Project description:BackgroundNSCLC (non-small-cell lung cancer) is the leading cause of cancer-related mortality worldwide. Both epigenetic and genetic changes contribute to the initiation, development and metastasis of NSCLC. Recently, accumulating data have begun to support the notion that long noncoding RNAs (lncRNAs) function as new crucial regulators of diverse biological processes, including proliferation, apoptosis and metastasis, and play crucial roles in tumorigenesis. Nevertheless, further study is warranted to comprehensively determine lncRNAs' functions and potential mechanism.MethodsIn this study, we performed a comprehensive analysis of the lncRNA expression profile of NSCLC using data from TCGA and Gene Expression Omnibus (GEO). PCAT6 expression level in a cohort of 60 pairs of NSCLC tissues using quantitative real-time PCR (qRT-PCR). Additionally, Loss-of-function assays and gain-of-function assays were used to assess the role of PCAT6 in promoting NSCLC progression. Tumor formation assay in a nude mouse model was performed to verity the role of PCAT6 in NSCLC in vivo. Meanwhile, RIP, ChIP, resue experiment and western blot assays were used to highlights the potential molecular mechanism of PCAT6 in NSCLC.FindingsWe identified that an oncogene, PCAT6, was upregulated in NSCLC, and this upregulation was verified in a cohort of 60 pairs of NSCLC tissues. Additionally, the expression level of PCAT6 was correlated with tumor size (P = .036), lymph node metastasis (P = .029) and TNM stage (P = .038). Loss-of-function and gain-of-function assays were used to assess the role of PCAT6 in promoting NSCLC progression. The results revealed that PCAT6 knockdown mitigated NSCLC cell growth by inducing G1-phase cell cycle arrest and apoptosis in vitro and in vivo. Whereas, PCAT6 overexpression could promoted tumor cell growth. Meanwhile, PCAT6 additionally promoted NSCLC cell migration and invasion. Furthermore, mechanistic investigation demonstrated that the oncogenic activity of PCAT6 is partially attributable to its repression of LATS2 via association with the epigenetic repressor EZH2 (Enhancer of zeste homolog 2). Overall, our study highlights the essential role of PCAT6 in NSCLC, suggesting that PCAT6 might be a potent therapeutic target for patients with NSCLC.

Project description:BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer-related death, and its biology remains poorly understood, especially in regards to the immunosuppression induced by immune checkpoints, such as Siglec-15. Most cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs display a better therapeutic effect in the clinic, including tumor progression inhibition and immunosuppression breaks. However, two or more drugs will result in a greater possibility of adverse effects. Thus, a double-function target is necessary for developing antitumor drugs, such as RNAi therapy.MethodsThe expression of TUG1, Siglec-15, and miRNAs was evaluated by qPCR, and protein expression was analyzed by western blotting. The immune responses were evaluated by a Jurkat-reporter gene assay, a T cell-induced cytotoxicity assay, and IFN-γ/IL-2 release. The interactions among TUG1, Siglec-15, and miRNAs were verified by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. CCK-8 and Transwell assays were used to determine tumor cell proliferation, migration, and invasion.ResultsIn HCC patients and cells, increased TUG1 levels were observed, positively regulating Siglec-15 expression. TUG1-induced Siglec-15 upregulation resulted in the suppression of the immune response of HCC cells. hsa-miR-582-5p directly targeted TUG1 and Siglec-15 mRNA, and ihsa-miR-582-5p knockout prevented the regulation of Siglec-15 induced by THU1. Changes in hsa-miR-582-5p expression negatively regulated Siglec-15 levels and immunosuppression but had no influence on TUG1 levels. siRNA knockdown of TUG1 effectively led to tumor progression inhibition and immune response improvement in HCC cells both in vitro and in vivo.ConclusionTUG1 increases the Siglec-15 level in HCC cells as a sponge to hsa-miR-582-5p, resulting in enhanced immunosuppression. TUG1 knockdown induced by siRNA not only reduces immunosuppression but also suppresses tumor progression both in vitro and in vivo. These novel findings may provide a potential and appropriate target for RNAi therapy to develop drugs with dual antitumor activity.

Dataset Information

Long noncoding RNA PCAT6 inhibits colon cancer cell apoptosis by regulating anti-apoptotic protein ARC expression via EZH2.

Publications

Long noncoding RNA PCAT6 inhibits colon cancer cell apoptosis by regulating anti-apoptotic protein ARC expression via EZH2.

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