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 HOXC10 mRNA 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. 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 HOXC10 mRNA 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. Long noncoding RNAs (lncRNAs) play a pivotal role in diverse physiological processes by gene regulation at the transcriptional and posttranscriptional levels (1Rinn J.L. Chang H.Y. Genome regulation by long noncoding RNAs.Annu. Rev. Biochem. 2012; 81: 145-166Crossref PubMed Scopus (2766) Google Scholar, 2Kornienko A.E. Guenzl P.M. Barlow D.P. Pauler F.M. Gene regulation by the act of long non-coding RNA transcription.BMC Biol. 2013; 11: 59Crossref PubMed Scopus (510) Google Scholar). For transcriptional regulation, lncRNAs recruit chromatin modifiers to promote epigenetic activation or silencing of gene expression. For example, lncRNA ANRIL recruits the polycomb repressive complex that mediates the transcriptional silencing by methylating the lysine 27 of histone H3 of the neighboring CDKN2A and CDKN2B genes (3Yap K.L. Li S. Munoz-Cabello A.M. Raguz S. Zeng L. Mujtaba S. Gil J. Walsh M.J. Zhou M.M. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a.Mol. Cell. 2010; 38: 662-674Abstract Full Text Full Text PDF PubMed Scopus (1068) Google Scholar). LncRNAs have also been reported to alter the DNA methylation of target genes: LncRNA Dum recruits Dnmt1, Dnmt3a, and Dnmt3b to the promoter of DPPA2 gene, thereby silencing its expression and stimulating myogenic differentiation (4Wang L. Zhao Y. Bao X. Zhu X. Kwok Y.K. Sun K. Chen X. Huang Y. Jauch R. Esteban M.A. Sun H. Wang H. LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration.Cell Res. 2015; 25: 335-350Crossref PubMed Scopus (161) Google Scholar). For posttranscriptional gene regulation, lncRNAs modulate mRNA splicing, mRNA turnover as well as translation and subcellular localization of target mRNAs (5Tripathi V. Shen Z. Chakraborty A. Giri S. Freier S.M. Wu X. Zhang Y. Gorospe M. Prasanth S.G. Lal A. Prasanth K.V. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of factor 2013; PubMed Scopus Google Scholar, S. M. A. R. A. regulation of expression formation is upregulated in 2013; PubMed Scopus Google Scholar, J. Y. Zhang X. J. Wang X. Li J. of with for factor gene unknown cell lung PubMed Scopus Google Scholar, Y. Zhang Y. Long noncoding RNA the of by HuR to mRNA PubMed Scopus Google Scholar, Zhang J. Wang M. Li X. H. H. Chen L. L. translation by and PubMed Scopus Google Scholar). is that with the target mRNA to mRNA stabilizes the mRNA K. Gorospe M. gene regulation by long noncoding Biol. 2013; PubMed Scopus Google Scholar). of with the target lncRNAs also as or to alter binding of transcriptional Wang Y. Y. Wang Wang Y. A. and of noncoding RNAs PubMed Scopus Google Scholar). gene regulation by lncRNAs is by with RNA-binding proteins which are known to modulate the and of target mRNAs K. Gorospe M. gene regulation by long noncoding Biol. 2013; PubMed Scopus Google Scholar). of the of RNA-binding are to associate with in the mRNA as and V. role in and PubMed Scopus Google Scholar). of mRNA by lncRNA in with binding highlights the role of complex in the regulation of mRNA L. Zhang Li J. Wu M. a long noncoding with to promote mRNA in human PubMed Scopus Google Scholar). complex with the of the of mRNA by lncRNA and complex is at its Y. M. K. L. S. M. M. M. J. K. a target lncRNA for mediates of to promote cell cycle Full Text Full Text PDF PubMed Scopus Google Scholar). of is the role of lncRNA which stabilizes or the with or J. Zhang A. Zhang Z. Zhou X. Zhang X. M. expression and Res. PubMed Scopus Google Scholar). the RBPs is the family HuR human known to to the at the of its target mRNAs R. K. Gene of for RNA binding gene family that is in and PubMed Scopus Google Scholar, M. Lal A. X. Gorospe M. of a target RNA for RNA-binding S. A. PubMed Scopus Google Scholar). of RBPs as and to RNA of transcripts, ELAV family proteins have an ELAV proteins the of RBPs with mRNA thereby of HuR, a protein, the in of J. PubMed Scopus Google Scholar, H. J. K. mRNA during in S. A. 2012; PubMed Scopus Google Scholar, of HuR in mRNA Cell. Biol. PubMed Scopus Google Scholar). are well as the for HuR that HuR also associate with many of HuR been with the the and the of S. M. M. mapping that the RNA-binding HuR and mRNA Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. H. binding of HuR and to a the of the Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). have the of in diverse to human V. Zhou H. S. S. Y. Chen lncRNA and by HuR in the 11: PubMed Scopus Google Scholar, Chang X. J.L. R. S. K. Gorospe M. of with mRNA myogenic gene Res. PubMed Scopus Google Scholar). of lncRNAs regulating HuR activity is LncRNA physically interacts with HuR and the of HuR, a lncRNA HuR in the its Y. Zhang Y. Long noncoding RNA the of by HuR to mRNA PubMed Scopus Google Scholar, V. Zhou H. S. S. Y. Chen lncRNA and by HuR in the 11: PubMed Scopus Google Scholar). is lncRNA which the of HuR by the X. X. Li X. X. Zhang X. Zhang S. Long noncoding RNA inhibits cell by of RNA-binding 11: PubMed Scopus Google Scholar). role of lncRNAs in the activity of HuR LncRNA physically with HuR as well as mRNA with which in the of mRNA Chang X. J.L. R. S. K. Gorospe M. of with mRNA myogenic gene Res. PubMed Scopus Google Scholar). of HuR binding to mRNA that as a for HuR binding to mRNA. is in to HuR binding to the of HuR activity by lncRNAs J. K. X. S. Gorospe M. LncRNA RNA-binding Res. PubMed Scopus Google Scholar). In this we that a lncRNA, LINC02381 as HOXC10 mRNA stabilizing factor or HMS in this the mRNA levels of HOXC10 is a of the gene family that also a role in S. genes and role in the of human PubMed Scopus Google Scholar, H. S. H. Zhou Y. Wang Y. Z. Y. Zhang Y. HOXC10 of with its PubMed Scopus Google Scholar, R. S. M. H. S. K. gene an epigenetic in lung Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). a of genes that are in and different regulation of genes by lncRNAs is by lncRNA that the of by the polycomb chromatin complex lncRNA, a complex with and the histone in methylation and transcriptional activation of the J.L. M. Wang X. Chang H.Y. of and chromatin in human by noncoding Full Text Full Text PDF PubMed Scopus Google Scholar, A. R. Chen Y. A. J. M. J. Chang H.Y. long noncoding RNA chromatin to gene PubMed Scopus Google Scholar). lncRNAs are in and with gene but role in gene regulation is to L. Wang Y. Zhang X. S. H. long non-coding RNAs in lung PubMed Scopus Google Scholar). LncRNA HMS discovered in a in the to identify that lncRNAs dysregulated in human are the to the by which HMS HOXC10 and discovered that does not alter the HOXC10 promoter but stabilizes the of HOXC10 mRNA. HMS its stretch to associate with the protein, HuR and recruit to the HOXC10 mRNA. we a lncRNA, HMS, functions as a HOXC10 mRNA stabilizing factor by with the HuR to stabilize HOXC10 which an role in the proliferation of cancer cells. of lncRNA cancer that majority of lncRNAs are cancer many lncRNAs have been discovered whose is a not cancer X. Z. Y. X. J. Zhao Zhang Y. L. L. J.L. Li of long non-coding RNAs human Cell. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). in we a for of dysregulated lncRNAs in lung adenocarcinoma gene expression of and the which lncRNAs the the whose mRNA and Genome expression and to identify upregulated or downregulated lncRNAs. and lncRNAs to upregulated and in with the lncRNAs dysregulated in cancer for in of analyzed to expression in and levels of the lncRNA and lncRNAs of lncRNAs are reported in the to have a role in cell proliferation and For example, lncRNA functions of to promote of cancer lncRNA of cell cell by the lncRNA the and lncRNA cell and Y. M. K. L. S. M. M. M. J. K. a target lncRNA for mediates of to promote cell cycle Full Text Full Text PDF PubMed Scopus Google Scholar, Long noncoding RNA cell and and is a in Rev. Google Scholar, Y. Zhang Li J. Wu X. X. Y. Long noncoding RNA to cell cycle and S. A. PubMed Scopus Google Scholar, Z. Sun M. Wang Y. Zhao Long non-coding RNA proliferation and of cell cell PubMed Scopus Google Scholar). lncRNAs and have been reported to promote and the of our to identify dysregulated lncRNAs Y. Wang S. Z. Zhang H. Zhang LncRNA cancer progression by silencing of and Cell. PubMed Scopus Google Scholar, X. H. Shen K. X. Y. Y. Long noncoding RNA lung adenocarcinoma and by binding with and Google Scholar, S. Zhang K. S. R. Y. A. L. S. lncRNA of cancer a role for in cancer PubMed Scopus Google Scholar). we the of lncRNAs is in cell that we the of lncRNA we the levels of the lncRNAs in an lung adenocarcinoma cell with a lung cell the proliferation of is that of and we that of lncRNAs HMS, and upregulated in and have the role of in and we are the role of lncRNAs but patient is not at we our in this by lncRNAs that are dysregulated cancer and in R. M.M. S. and by Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, A. M. V. R. R. M.M. S. inhibition of the is in Biol. 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