Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The lncRNA HMS recruits RNA-binding protein HuR to stabilize the 3'-UTR of HOXC10 mRNA.

ABSTRACT: Long noncoding RNAs (lncRNAs) have been reported to drive key cancer pathways but the functions of majority of lncRNAs are unknown making a case for comprehensive functional evaluation of lncRNAs. With an aim to identify lncRNAs dysregulated in human cancers, we analyzed the cancer patient database of lung adenocarcinoma (LUAD), which revealed an upregulated lncRNA, LINC02381 (renamed HOXC10mRNA stabilizing factor or HMS in this study), whose depletion results in proliferation defects and inhibition of colony formation of human cancer cells. In order to identify the binding targets of HMS, we screened for cis-genes and discovered that HOXC10, an oncogene, is downregulated in the absence of HMS. Depletion of HMS does not affect the HOXC10 promoter activity but inhibits the HOXC10 3'-UTR-linked luciferase reporter activity. Since lncRNAs have been known to associate with RNA-binding proteins (RBPs) to stabilize mRNA transcripts, we screened for different RBPs and discovered that HuR, an ELAV family protein, stabilizes HOXC10 mRNA. Using RNA pull-down and deletion mapping experiments, we show that HuR physically interacts with the cytosine-rich stretch of HMS and HOXC10 3'-UTR to stabilize HOXC10 mRNA. HOXC10 is overexpressed in many human cancers, and our discovery highlights that lncRNA HMS sustains the HOXC10 mRNA levels to maintain the invasive phenotypes of cancer cells.

SUBMITTER: Priyanka P

PROVIDER: S-EPMC8363838 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

LncRNA OIP5-AS1/cyrano sponges RNA-binding protein HuR.

Project description:The function of the vast majority of mammalian long noncoding (lnc) RNAs remains unknown. Here, analysis of a highly abundant mammalian lncRNA, OIP5-AS1, known as cyrano in zebrafish, revealed that OIP5-AS1 reduces cell proliferation. In human cervical carcinoma HeLa cells, the RNA-binding protein HuR, which enhances cell proliferation, associated with OIP5-AS1 and stabilized it. Tagging OIP5-AS1 with MS2 hairpins to identify associated microRNAs revealed that miR-424 interacted with OIP5-AS1 and competed with HuR for binding to OIP5-AS1. We further identified a 'sponge' function for OIP5-AS1, as high levels of OIP5-AS1 increased HuR-OIP5-AS1 complexes and prevented HuR interaction with target mRNAs, including those that encoded proliferative proteins, while conversely, lowering OIP5-AS1 increased the abundance of HuR complexes with target mRNAs. We propose that OIP5-AS1 serves as a sponge or a competing endogenous (ce)RNA for HuR, restricting its availability to HuR target mRNAs and thereby repressing HuR-elicited proliferative phenotypes.

| S-EPMC4797289 | biostudies-literature

Triciribine Engages ZFP36L1 and HuR to Stabilize LDLR mRNA.

Project description:An increased understanding of low-density lipoprotein receptor (LDLR) and its regulation may facilitate drug development for the treatment of hypercholesterolemia. Triciribine (TCN), which is a highly selective AKT inhibitor, increases the stability of LDLR mRNA downstream of extracellular signal-regulated kinase (ERK) in human hepatoma cells (HepG2). Here, a candidate approach was used in order to determine whether the RNA-binding proteins (RBPs) ZFP36 ring finger protein like 1 (ZFP36L1) and Hu antigen R (HuR) play a role in TCN-mediated stabilization of LDLR mRNA. The depletion of HuR led to a reduction of LDLR mRNA stability, an event that was more pronounced in TCN-treated cells. TCN was found to induce the translocation of nuclear HuR to cytoplasm in an ERK-dependent manner. ZFP36L1 depletion increased the stability of LDLR mRNA consistent with its destabilizing role. However, in contrast to HuR, TCN had no effect on LDLR mRNA turnover in ZFP36L1-depleted cells. TCN induced the phosphorylation of ZFP36L1 in an ERK/RSK-dependent manner and promoted its dissociation from the CCR4-NOT complex. In sum, these data suggest that TCN utilizes ERK signaling to increase the activity of HuR and inhibit ZFP36L1 to stabilize LDLR mRNA in HepG2 cells.

| S-EPMC7583736 | biostudies-literature

Hypoxia-induced lncRNA MRVI1-AS1 accelerates hepatocellular carcinoma progression by recruiting RNA-binding protein CELF2 to stabilize SKA1 mRNA.

Project description:BackgroundLong non-coding RNAs (lncRNAs) perform a vital role during the progression of hepatocellular carcinoma (HCC). Here, we aimed to identify a novel lncRNA involved in HCC development and elucidate the underlying molecular mechanism.MethodsThe RT-qPCR and TCGA dataset analysis were applied to explore the expressions of MRVI1-AS1 in HCC tissues and cell lines. Statistical analysis was applied to analyze the clinical significance of MRVI1-AS1 in HCC. The functions of MRVI1-AS1 in HCC cells metastasis and growth were explored by transwell assays, wound healing assay, MTT assay, EdU assay, the intravenous transplantation tumor model, and the subcutaneous xenograft tumor model. Microarray mRNA expression analysis, dual luciferase assays, and actinomycin D treatment were used to explore the downstream target of MRVI1-AS1 in HCC cells. RIP assay was applied to assess the direct interactions between CELF2 and MRVI1-AS1 or SKA1 mRNA. Rescue experiments were employed to validate the functional effects of MRVI1-AS1, CELF2, and SKA1 on HCC cells.ResultsMRVI1-AS1 was found to be dramatically upregulated in HCC and the expression was strongly linked to tumor size, venous infiltration, TNM stage, as well as HCC patients' outcome. Cytological experiments and animal experiments showed that MRVI1-AS1 promoted HCC cells metastasis and growth. Furthermore, SKA1 was identified as the downstream targeted mRNA of MRVI1-AS1 in HCC cells, and MRVI1-AS1 increased SKA1 expression by recruiting CELF2 protein to stabilize SKA1 mRNA. In addition, we found that MRVI1-AS1 expression was stimulated by hypoxia through a HIF-1-dependent manner, which meant that MRVI1-AS was a direct downstream target gene of HIF-1 in HCC.ConclusionIn a word, our findings elucidated that hypoxia-induced MRVI1-AS1 promotes metastasis and growth of HCC cells via recruiting CELF2 protein to stabilize SKA1 mRNA, pointing to MRVI1-AS1 as a promising clinical application target for HCC therapy.

| S-EPMC10044719 | biostudies-literature

AUF1 and HuR proteins stabilize interleukin-8 mRNA in human saliva.

Project description:Human saliva contains thousands of mRNAs, some of which have translational value as diagnostic markers for human diseases. We have found that more than 30% of the mRNAs detected in human saliva contain AU-rich elements (ARE) in their 3' untranslated regions (3'UTR). Since AREs are known to contribute to RNA turnover by forming complexes with ARE-binding proteins, we hypothesized that salivary mRNA stability is mediated by ARE-binding proteins in human saliva. To test this hypothesis, we monitored the in vitro degradation of a radiolabeled ARE-containing salivary mRNA (IL-8) in salivary protein extracts. The degradation of IL-8 mRNA was accelerated by competition for saliva ARE-binding proteins through the addition of excess unlabeled IL-8 mRNA fragments containing 4 tandem AREs. UV cross-linking and immunoprecipitation experiments revealed 2 ARE-binding proteins, AUF1 and HuR, associated with IL-8 mRNA in saliva. These results demonstrate that ARE-binding proteins contribute to the stability of ARE mRNAs in human saliva.

| S-EPMC2572714 | biostudies-literature

The lncRNA ZFAS1 regulates lipogenesis in colorectal cancer by binding polyadenylate-binding protein 2 to stabilize SREBP1 mRNA.

Project description:Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality globally. Therefore, a better understanding of the early molecular events of this disease is needed. Long noncoding RNAs (lncRNAs) play a critical role in the regulation of tumorigenesis and cancer progression. In this study, we investigated the characteristics of ZFAS1 in CRC. We analyzed three independent microarray datasets of CRC tissues from GEO and found that ZFAS1 expression was remarkably upregulated in all three datasets. Moreover, we validated the overexpression of ZFAS1 in CRC tissues compared with normal tissues and found that ZFAS1 was positively correlated with tumor size and metastasis in CRC. Knockdown of ZFAS1 significantly suppressed the malignant phenotype and lipogenesis of CRC cells. Mechanistically, ZFAS1 binds polyadenylate-binding protein 2 (PABP2) to stabilize SREBP1 mRNA, thereby increasing the expression of SREBP1 and its target genes stearoyl-CoA desaturase (SCD1) and fatty acid synthase (FASN), thus promoting CRC lipid accumulation. These data demonstrated that ZFAS1 could act as an oncogene for CRC and that ZFAS1 reprograms lipid metabolism by binding with PABP2 to stabilize SREBP1 mRNA accumulation, implicating it as a novel and potent target for the treatment of CRC.

| S-EPMC8728310 | biostudies-literature

RPSAP52 lncRNA Inhibits p21Waf1/CIP Expression by Interacting With the RNA Binding Protein HuR.

Project description:Long noncoding RNAs have been recently demonstrated to have an important role in fundamental biological processes, and their deregulated expression has been found in several human neoplasias. Our group has recently reported a drastic overexpression of the long noncoding RNA (lncRNA) RPSAP52 (ribosomal protein SA pseudogene 52) in pituitary adenomas. We have shown that this lncRNA increased cell proliferation by upregulating the expression of the chromatinic proteins HMGA1 and HMGA2, functioning as a competing endogenous RNA (ceRNA) through competitively binding to microRNA-15a (miR-15a), miR-15b, and miR-16. The aim of this work was to identify further mechanisms by which RPSAP52 overexpression could contribute to the development of pituitary adenomas. We investigated the involvement of RPSAP52 in the modulation of the expression of cell cycle-related genes, such as p21Waf1/CIP, whose deregulation plays a critical role in pituitary cell transformation. We report that RPSAP52, interacting with the RNA binding protein HuR (human antigen R), favors the delocalization of miR-15a, miR-15b, and miR-16 on the cyclin-dependent kinase inhibitor p21Waf1/CIP1 that, accordingly, results in downregulation in pituitary adenomas. A RNA immunoprecipitation sequencing (RIPseq) analysis performed on cells overexpressing RPSAP52 identified 40 messenger RNAs (mRNAs) enriched in Argonaute 2 (AGO2) immunoprecipitated samples. Among them, we focused on GAS8 (growth arrest-specific protein 8) gene. Consistently, GAS8 expression was downregulated in all the analyzed pituitary adenomas with respect to normal pituitary and in RPSAP52-overepressing cells, supporting the role of RPSAP52 in addressing genes involved in growth inhibition and cell cycle arrest to miRNA-induced degradation. This study unveils another RPSAP52-mediated molecular mechanism in pituitary tumorigenesis.

| S-EPMC7851518 | biostudies-literature

RNA-binding proteins La and HuR cooperatively modulate translation repression of PDCD4 mRNA.

Project description:Posttranscriptional regulation of gene expression plays a critical role in controlling the inflammatory response. An uncontrolled inflammatory response results in chronic inflammation, often leading to tumorigenesis. Programmed cell death 4 (PDCD4) is a proinflammatory tumor-suppressor gene which helps to prevent the transition from chronic inflammation to cancer. PDCD4 mRNA translation is regulated by an interplay between the oncogenic microRNA miR-21 and the RNA-binding protein (RBP) human antigen R (HuR) in response to lipopolysaccharide stimulation, but the role of other regulatory factors remains unknown. Here, we report that the RBP lupus antigen (La) interacts with the 3'-untranslated region of PDCD4 mRNA and prevents miR-21-mediated translation repression. While lipopolysaccharide causes nuclear-cytoplasmic translocation of HuR, it enhances cellular La expression. Remarkably, La and HuR were found to bind cooperatively to the PDCD4 mRNA and mitigate miR-21-mediated translation repression. The cooperative action of La and HuR reduced cell proliferation and enhanced apoptosis, reversing the pro-oncogenic function of miR-21. Together, these observations demonstrate a cooperative interplay between two RBPs, triggered differentially by the same stimulus, which exerts a synergistic effect on PDCD4 expression and thereby helps maintain a balance between inflammation and tumorigenesis.

| S-EPMC7949077 | biostudies-literature

The RNA-binding protein HuR regulates DNA methylation through stabilization of DNMT3b mRNA.

Project description:The molecular basis underlying the aberrant DNA-methylation patterns in human cancer is largely unknown. Altered DNA methyltransferase (DNMT) activity is believed to contribute, as DNMT expression levels increase during tumorigenesis. Here, we present evidence that the expression of DNMT3b is post-transcriptionally regulated by HuR, an RNA-binding protein that stabilizes and/or modulates the translation of target mRNAs. The presence of a putative HuR-recognition motif in the DNMT3b 3'UTR prompted studies to investigate if this transcript associated with HuR. The interaction between HuR and DNMT3b mRNA was studied by immunoprecipitation of endogenous HuR ribonucleoprotein complexes followed by RT-qPCR detection of DNMT3b mRNA, and by in vitro pulldown of biotinylated DNMT3b RNAs followed by western blotting detection of HuR. These studies revealed that binding of HuR stabilized the DNMT3b mRNA and increased DNMT3b expression. Unexpectedly, cisplatin treatment triggered the dissociation of the [HuR-DNMT3b mRNA] complex, in turn promoting DNMT3b mRNA decay, decreasing DNMT3b abundance, and lowering the methylation of repeated sequences and global DNA methylation. In summary, our data identify DNMT3b mRNA as a novel HuR target, present evidence that HuR affects DNMT3b expression levels post-transcriptionally, and reveal the functional consequences of the HuR-regulated DNMT3b upon DNA methylation patterns.

| S-EPMC2677878 | biostudies-other

Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability.

Project description:RNA-binding proteins coordinate the fates of multiple RNAs, but the principles underlying these global interactions remain poorly understood. We elucidated regulatory mechanisms of the RNA-binding protein HuR, by integrating data from diverse high-throughput targeting technologies, specifically PAR-CLIP, RIP-chip, and whole-transcript expression profiling. The number of binding sites per transcript, degree of HuR association, and degree of HuR-dependent RNA stabilization were positively correlated. Pre-mRNA and mature mRNA containing both intronic and 3' UTR binding sites were more highly stabilized than transcripts with only 3' UTR or only intronic binding sites, suggesting that HuR couples pre-mRNA processing with mature mRNA stability. We also observed HuR-dependent splicing changes and substantial binding of HuR in polypyrimidine tracts of pre-mRNAs. Comparison of the spatial patterns surrounding HuR and miRNA binding sites provided functional evidence for HuR-dependent antagonism of proximal miRNA-mediated repression. We conclude that HuR coordinates gene expression outcomes at multiple interconnected steps of RNA processing.

| S-EPMC3220597 | biostudies-literature

MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90.

Project description:The mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) plays a major role in dephosphorylating and thereby inactivating the MAP kinases extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Here, we examine the posttranscriptional events underlying the robust MKP-1 induction by oxidants in HeLa cells. H(2)O(2) treatment potently stabilized the MKP-1 mRNA and increased the association of MKP-1 mRNA with the translation machinery. Four RNA-binding proteins (RNA-BPs) that influence mRNA turnover and/or translation (HuR, NF90, TIAR, and TIA-1) were found to bind to biotinylated transcripts spanning the MKP-1 AU-rich 3' untranslated region. By using ribonucleoprotein immunoprecipitation analysis, we showed that H(2)O(2) treatment increased the association of MKP-1 mRNA with HuR and NF90 and decreased its association with the translational repressors TIAR and TIA-1. HuR or NF90 silencing significantly diminished the H(2)O(2)-stimulated MKP-1 mRNA stability; HuR silencing also markedly decreased MKP-1 translation. In turn, lowering MKP-1 expression in HuR-silenced cultures resulted in substantially elevated phosphorylation of JNK and p38 after H(2)O(2) treatment. Collectively, MKP-1 upregulation by oxidative stress is potently influenced by increased mRNA stability and translation, mediated at least in part by the RNA-BPs HuR and NF90.

| S-EPMC2447119 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data