TRA2A Binds With LncRNA MALAT1 To Promote Esophageal Cancer Progression By Regulating EZH2/β-catenin Pathway.
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ABSTRACT:
SUBMITTER: Zhao X
PROVIDER: S-EPMC8247389 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) is one type of cancers whose carcinogenesis and progression are closely related to chronic inflammation. Identifying the molecular mechanisms for inflammation-related HCC progression will contribute to improve the efficacy of current therapeutics for HCC patients. Many kinds of epigenetic factors, including long non-coding RNAs (lncRNAs), have been discovered to be important in HCC growth and metastasis. However, how the lncRNAs promote HCC progression and what's the application of lncRNA silencing in vivo in suppressing HCC remain to be further investigated. Here, we found that lncRNA metastasis associated lung adenocarcinoma transcript1 (MALAT1) was upregulated in HCC tumor tissues, and knockdown of MALAT1 suppressed proliferation, cell cycle and invasion of HCC cells in response to lipopolysaccharide (LPS) stimulation. Knockdown of MALAT1 significantly inhibited LPS-induced pro-inflammatory mediators IL-6 and CXCL8 expression in HCC cells, which could be restored by overexpressing MALAT1. Mechanistically, MALAT1 recruited Brahma-related gene 1 (BRG1), a catalytic subunit of chromatin remodeling complex switching/sucrose non-fermentable (SWI/SNF), to the promoter region of IL-6 and CXCL8, and thus facilitated NF-?B to induce the expression of these inflammatory factors. Importantly, in vivo silencing of MALAT1 in HCC tissues inhibited growth of HCC xenografts, and also suppressed the expression of pro-inflammatory factors in HCC tissues accordingly. Our results demonstrate that MALAT1 promotes HCC progression by binding BRG1 to epigenetically enhance inflammatory response in HCC tissues, and silencing of MALAT1 may be a potential approach to the treatment of HCC.
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Project description:Evidences have shown that lncRNAs involve in the initiation and progression of various cancers including esophageal squamous cell carcinoma (ESCC). The aberrant expression of lncRNA MALAT1 was investigated in 106 paired ESCC tissues and adjacent non-cancerous tissues by qRT-PCR. Down-regulated MALAT1 and Ezh2 over-expression plasmid were constructed respectively to analyze the expression of β-catenin, Lin28 and Ezh2 genes. We found that the MALAT1 expression level was higher in human ESCC tissues (P=0.0011), which was closely correlated with WHO grade (P=0.0395, P=0.0331), lymph node metastasis (P=0.0213) and prognosis (P=0.0294). Silencing of MALAT1 expression inhibited cell proliferation, migration and tumor sphere formation, while increasing cell apoptosis of esophageal cancer in vitro. Down-regulation of MALAT1 decreased the expression of β-catenin, Lin28 and Ezh2 genes, while over-expressed Ezh2 combined with MALAT1 down-regulation completely reversed the si-MALAT1-mediated repression of β-catenin and Lin28 in esophageal cancer cells. Animal experiments showed that knockdown of MALAT1 decreased tumor formation and improved survival. MALAT1 promotes the initiation and progression of ESCC, suggesting that inhibition of MALAT1 might be a potential target for treatment of ESCC.
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Project description:Transformer 2 alpha homolog (TRA2A), a member of the serine/arginine-rich splicing factor family, has been shown to control mRNA splicing in development and cancers. However, it remains unclear whether TRA2A is involved in lncRNA regulation. In the present study, we found that TRA2A was upregulated and correlated with poor prognosis in esophageal cancer. Downregulation of TRA2A suppressed the tumor growth in xenograft nude mice. Epitranscriptomic microarray showed that depletion of TRA2A affected global lncRNA methylation similarly to the key m6 A methyltransferase, METTL3, by silencing. MeRIP-qPCR, RNA pull-down, CLIP analyses, and stability assays indicated that ablation of TRA2A reduced m6 A-modification of the oncogenic lncRNA MALAT1, thus inducing structural alterations and reduced stability. Furthermore, Co-IP experiments showed TRA2A directly interacted with METTL3 and RBMX, which also affected the writer KIAA1429 expression. Knockdown of TRA2A inhibited cell proliferation in a manner restored by RBMX/KIAA1429 overexpression. Clinically, MALAT1, RBMX, and KIAA1429 were prognostic factors of worse survival in ESCA patients. Structural similarity-based virtual screening in FDA-approved drugs repurposed nebivolol, a β1 -adrenergic receptor antagonist, as a potent compound to suppress the proliferation of esophageal cancer cells. Cellular thermal shift and RIP assay indicated that nebivolol may compete with MALAT1 to bind TRA2A. In conclusion, our study revealed the noncanonical function of TRA2A, which coordinates with multiple methylation proteins to promote oncogenic MALAT1 during ESCA carcinogenesis.
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Project description:Mantle cell lymphoma (MCL) is considered an aggressive subtype of non-Hodgkin's lymphoma with variable treatment responses. There is an urgent need to identify novel markers with prognostic and therapeutic value for MCL. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancers, including MCL. Metastasis-associated lung adenocarcinoma transcript 1(MALAT1), a lncRNA located at pathognomonic translocation site of t (11; 14) of MCL. MALAT1 is known to be overexpressed in solid tumors and hematologic malignancies. However, the pathological role and clinical relevance of MALAT1 in MCL are not completely understood.We quantified MALAT1 in MCL samples (40) and CD19+ B cells by quantitative real time polymerase chain reaction (qRT-PCR) and correlated levels with clinical outcome. We silenced MALAT1 in MCL cell lines and analyzed cells in tumorigenic assays and formation of transcription complexes.We found that the expression of MALAT1 was elevated in human MCL tumors and cell lines as compared to normal controls, and the elevated levels of MALAT1 correlated with higher MCL international prognostic index (MIPI) and reduced overall survival. MCL with knockdown of MALAT1 showed impaired cell proliferation, facilitated apoptosis and produced fewer clonogenic foci. The increased expression of p21 and p27 upon MALAT1 knockdown was regulated by enhancer of zeste homolog 2 (EZH2). Moreover, decreased phosphorylation of EZH2 at T350 attenuated the binding to MALAT1.Our findings illuminate the oncogenic role of MALAT1, which may serve as a novel biomarker and as a therapeutic target in MCL.
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Project description:The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody-based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3' end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT-qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC.
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Project description:BackgroundAbnormal 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.MethodsMicroarrays 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.ResultsESCC 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.ConclusionsOur 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.
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Project description:Background: Hepatocellular carcinoma (HCC) is a prominent cancer type, with long non-coding RNAs (lncRNAs) being known to be relevant to its progression. We therefore investigated how a particular lncRNA known as the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was associated with HCC. Methods: Quantitative reverse transcriptase PCR (qPCR) was used to assess expression of MALAT1, Forkhead Box M1 (FOXM1) and miR-125a-3p in HCC tissue samples. How MALAT1 regulates HCC proliferation and metastasis was assessed through appropriate assays. FOXM1 was identified as a miR-125a-3p target using luciferase assays, and how MALAT1/miR-125a-3p alter FOXM1 expression was explored via qPCR and Western blotting. Results: HCC tissues exhibited MALAT1 upregulation. miR-125a-3p targeted FOXM1 and could be regulated by MALAT1. MALAT1 knockdown disrupted proliferation and invasion, whereas miR-125a-3p knockdown partially reversed this phenotype. Conclusions: These results indicate that MALAT1 modulates FOXM1 expression via being a miR-125a-3p sponge, thus promoting HCC progression.
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Project description:Background:Increasing investigations indicate that long noncoding RNA (lncRNA) is responsible for diverse biological functions during the progression of cancer. However, its functions and underlying mechanisms remain elusive. Here, we investigated the MAFG-AS1- expression profile in esophageal squamous-cell carcinoma (ESCC) patients and explored its biological function and potential molecular mechanisms. Methods:qRT-PCR and the GEPIA data base were used to evaluate expression levels of MAFG-AS1 in ESCC tissue and cells. WST1-proliferation, -migration, and -invasion assays were performed to define the role of MAFG-AS1 in ESCC. Potential molecular mechanisms of MAFG-AS1 were investigated with online bioinformatic analysis, qRT-PCR, and rescue assays. Results:MAFG-AS1 was upregulated in 45 ESCC-tissue samples and cell lines compared to that of adjacent nontumor tissue and normal esophageal cells. Higher MAFG-AS1 expressionindicated poor survival. Gain- and loss-of-function experiments suggested that MAFG-AS1 promoted ESCC-cell proliferation, migration, and invasion. Molecular mechanism analysis and rescue assay showed that miR143 inhibitors partly abolished the suppression of MAFG-AS1 knockdown on EC109-cells proliferation. Moreover, we found that LASP1 specifically targeted miR143. Collectively, these data indicated that MAFG-AS1 served as a ceRNA to elevate LASP1 levels by sponging miR143, and played an oncogenic role in ESCC. Conclusion:Our research findings demonstrate that MAFG-AS1 is a key regulator through a novel MAFG-AS1-miR143-LASP1 axis in ESCC development and progression, which may offer a potential therapeutic target for ESCC.
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