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• W3022019982 abstract "Glioma is a brain cancer characterized by strong invasiveness with limited treatment options and poor prognosis. Recently, dysregulation of long non-coding RNAs (lncRNAs) has emerged as an important component in cellular processes and tumorigenesis. In this study, we demonstrated that TATA-box binding protein associated factor 15 (TAF15) and long intergenic non-protein coding RNA 665 (LINC00665) were both downregulated in glioma tissues and cells. TAF15 overexpression enhanced the stability of LINC00665, inhibiting malignant biological behaviors of glioma cells. Both metal regulatory transcription factor 1 (MTF1) and YY2 transcription factor (YY2) showed high expression levels in glioma tissues and cells, and their knockdown inhibited malignant progression. Mechanistically, overexpression of LINC00665 was confirmed to destabilize MTF1 and YY2 mRNA by interacting with STAU1, and knockdown of STAU1 could rescue the MTF1 and YY2 mRNA degradation caused by LINC00665 overexpression. G2 and S-phase expressed 1 (GTSE1) was identified as an oncogene in glioma, and knockdown of MTF1 or YY2 decreased the mRNA and protein expression levels of GTSE1 through direct binding to the GTSE1 promoter region. Our study highlights a key role of the TAF15/LINC00665/MTF1(YY2)/GTSE1 axis in modulating the malignant biological behaviors of glioma cells, suggesting novel mechanisms by which lncRNAs affect STAU1-mediated mRNA stability, which can inform new molecular therapies for glioma. Glioma is a brain cancer characterized by strong invasiveness with limited treatment options and poor prognosis. Recently, dysregulation of long non-coding RNAs (lncRNAs) has emerged as an important component in cellular processes and tumorigenesis. In this study, we demonstrated that TATA-box binding protein associated factor 15 (TAF15) and long intergenic non-protein coding RNA 665 (LINC00665) were both downregulated in glioma tissues and cells. TAF15 overexpression enhanced the stability of LINC00665, inhibiting malignant biological behaviors of glioma cells. Both metal regulatory transcription factor 1 (MTF1) and YY2 transcription factor (YY2) showed high expression levels in glioma tissues and cells, and their knockdown inhibited malignant progression. Mechanistically, overexpression of LINC00665 was confirmed to destabilize MTF1 and YY2 mRNA by interacting with STAU1, and knockdown of STAU1 could rescue the MTF1 and YY2 mRNA degradation caused by LINC00665 overexpression. G2 and S-phase expressed 1 (GTSE1) was identified as an oncogene in glioma, and knockdown of MTF1 or YY2 decreased the mRNA and protein expression levels of GTSE1 through direct binding to the GTSE1 promoter region. Our study highlights a key role of the TAF15/LINC00665/MTF1(YY2)/GTSE1 axis in modulating the malignant biological behaviors of glioma cells, suggesting novel mechanisms by which lncRNAs affect STAU1-mediated mRNA stability, which can inform new molecular therapies for glioma. Glioma is one of the most common and lethal primary malignant tumors of the brain, and it is classified into four categories: low-grade glioma (including categories I and II) and high-grade glioma (including categories III and IV), according to World Health Organization grading criteria.1Andersson M.K. Ståhlberg A. Arvidsson Y. Olofsson A. Semb H. Stenman G. Nilsson O. Aman P. The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response.BMC Cell Biol. 2008; 9: 37Crossref PubMed Scopus (243) Google Scholar,2Ballarino M. Jobert L. Dembélé D. de la Grange P. Auboeuf D. Tora L. TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs.Oncogene. 2013; 32: 4646-4655Crossref PubMed Scopus (33) Google Scholar High-grade glioma cells easily infiltrate the extracellular matrix of human brain cells, which is a major challenge for achieving a radical cure, especially using traditional methods such as surgery, radiotherapy, and chemotherapy.3Barresi V. Trovato-Salinaro A. Spampinato G. Musso N. Castorina S. Rizzarelli E. Condorelli D.F. Transcriptome analysis of copper homeostasis genes reveals coordinated upregulation of SLC31A1, SCO1, and COX11 in colorectal cancer.FEBS Open Bio. 2016; 6: 794-806Crossref PubMed Scopus (52) Google Scholar,4Chai Y. Liu J. Zhang Z. Liu L. HuR-regulated lncRNA NEAT1 stability in tumorigenesis and progression of ovarian cancer.Cancer Med. 2016; 5: 1588-1598Crossref PubMed Scopus (139) Google Scholar Therefore, identifying tumor biomarkers and developing molecular targeted therapies for glioma have become important research goals for improving the prognosis of patients with glioma. In the present study, we focused on the expression of long non-coding RNAs (lncRNAs) and potential interacting factors in glioma to highlight new potential targets for treatment or diagnosis, as well as to gain new insight into the mechanisms of glioma malignant transformation. The important roles of RNAs and their regulatory mechanisms in physiological and pathological processes, including tumorigenesis, are increasingly being revealed and recognized as candidate targets for biomarkers and cancer treatments. lncRNAs are a class of endogenous RNA molecules with transcripts longer than 200 nt and limited protein-coding potential.5Chen L. Shioda T. Coser K.R. Lynch M.C. Yang C. Schmidt E.V. Genome-wide analysis of YY2 versus YY1 target genes.Nucleic Acids Res. 2010; 38: 4011-4026Crossref PubMed Scopus (40) Google Scholar Several lncRNAs have been identified to act as either oncogenes or tumor suppressors, regulating the biological process of the tumor cell cycle and tumorigenesis.6Chen R. Smith-Cohn M. Cohen A.L. Colman H. Glioma subclassifications and their clinical significance.Neurotherapeutics. 2017; 14: 284-297Crossref PubMed Scopus (346) Google Scholar Accumulating evidence indicates that RNA-binding proteins (RBPs) directly bind to and stabilize lncRNAs to regulate tumor biological processes.7Cho H. Kim K.M. Han S. Choe J. Park S.G. Choi S.S. Kim Y.K. Staufen1-mediated mRNA decay functions in adipogenesis.Mol. Cell. 2012; 46: 495-506Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar For instance, HuR was found to stabilize lncRNA HOTAIR to promote its expression in head and neck squamous cell carcinoma.8Cimadamore A. Gasparrini S. Mazzucchelli R. Doria A. Cheng L. Lopez-Beltran A. Santoni M. Scarpelli M. Montironi R. Long non-coding RNAs in prostate cancer with emphasis on second chromosome locus associated with prostate-1 expression.Front. Oncol. 2017; 7: 305Crossref PubMed Scopus (17) Google Scholar HuR also functions as a tumor facilitator in ovarian cancer by enhancing the stability of lncRNA NEAT1 to promote malignant progression.9Cong Z. Diao Y. Xu Y. Li X. Jiang Z. Shao C. Ji S. Shen Y. De W. Qiang Y. Long non-coding RNA linc00665 promotes lung adenocarcinoma progression and functions as ceRNA to regulate AKR1B10-ERK signaling by sponging miR-98.Cell Death Dis. 2019; 10: 84Crossref PubMed Scopus (93) Google Scholar The lncRNA CRNDE could be stabilized by hnRNPUL2, thereby accelerating cell proliferation and migration in colorectal carcinoma.10Damas N.D. Marcatti M. Côme C. Christensen L.L. Nielsen M.M. Baumgartner R. Gylling H.M. Maglieri G. Rundsten C.F. Seemann S.E. et al.SNHG5 promotes colorectal cancer cell survival by counteracting STAU1-mediated mRNA destabilization.Nat. Commun. 2016; 7: 13875Crossref PubMed Scopus (155) Google Scholar The dynamic complex of RNAs and RBPs mediates virtually all stages of the RNA life cycle, and dysfunction in RBPs can cause changes to the transcriptome and proteome of the cell, leading to tumor growth and aberrant biological behaviors.11Gao Y. Yu H. Liu Y. Liu X. Zheng J. Ma J. Gong W. Chen J. Zhao L. Tian Y. Xue Y. Long non-coding RNA HOXA-AS2 regulates malignant glioma behaviors and vasculogenic mimicry formation via the miR-373/EGFR axis.Cell. Physiol. Biochem. 2018; 45: 131-147Crossref PubMed Scopus (72) Google Scholar,12Gong C. Maquat L.E. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements.Nature. 2011; 470: 284-288Crossref PubMed Scopus (950) Google Scholar TATA-box binding protein associated factor 15 (TAF15), a member of the FET family, plays an important role in regulating mRNA transcription, RNA splicing, and transportation, and it shows a high translocation rate in certain malignant tumors such as liposarcoma and Ewing’s sarcoma.13Gong C. Tang Y. Maquat L.E. mRNA-mRNA duplexes that autoelicit Staufen1-mediated mRNA decay.Nat. Struct. Mol. Biol. 2013; 20: 1214-1220Crossref PubMed Scopus (51) Google Scholar, 14Guo B. Wu S. Zhu X. Zhang L. Deng J. Li F. Wang Y. Zhang S. Wu R. Lu J. et al.Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression.EMBO J. 2020; 39: e102190Crossref PubMed Scopus (87) Google Scholar, 15Guo L. Zhang S. Zhang B. Chen W. Li X. Zhang W. Zhou C. Zhang J. Ren N. Ye Q. Silencing GTSE-1 expression inhibits proliferation and invasion of hepatocellular carcinoma cells.Cell Biol. Toxicol. 2016; 32: 263-274Crossref PubMed Scopus (28) Google Scholar TAF15 was also shown to promote the proliferation of human neuroblastoma cells via altering gene expression through a microRNA-involved pathway.16Gusyatiner O. Hegi M.E. Glioma epigenetics: from subclassification to novel treatment options.Semin. Cancer Biol. 2018; 51: 50-58Crossref PubMed Scopus (257) Google Scholar Therefore, we examined the expression of TAF15 in glioma tissues and cells and used microarray analysis to identify differentially expressed lncRNAs in TAF15-overexpressed glioma cells. Among the candidates, the downregulated long intergenic non-protein coding RNA 665 (LINC00665) in glioma sparked our interest. Studies suggest that LINC00665 contributes to a high risk of oral premalignant lesions.17Haroon Z.A. Amin K. Lichtlen P. Sato B. Huynh N.T. Wang Z. Schaffner W. Murphy B.J. Loss of metal transcription factor-1 suppresses tumor growth through enhanced matrix deposition.FASEB J. 2004; 18: 1176-1184Crossref PubMed Scopus (32) Google Scholar STAU1-mediated mRNA decay (SMD) is a common mRNA degradation process in mammalian cells, which regulates numerous biological processes, including myogenesis, keratinocyte-mediated wound healing, and adipogenesis.18He X. Ma Q. Induction of metallothionein I by arsenic via metal-activated transcription factor 1: critical role of C-terminal cysteine residues in arsenic sensing.J. Biol. Chem. 2009; 284: 12609-12621Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar,19Huang L. Yan M. Kirschke C.P. Over-expression of ZnT7 increases insulin synthesis and secretion in pancreatic β-cells by promoting insulin gene transcription.Exp. Cell Res. 2010; 316: 2630-2643Crossref PubMed Scopus (45) Google Scholar This pathway involves STAU1, a double-stranded RBP, that recognizes the STAU1-binding site (SBS) as a complementary double-stranded RNA structure formed either by intramolecular or intermolecular base pairing of the target mRNA 3′ untranslated region (UTR) and lncRNA.20Jiang H. Wang Y. Ai M. Wang H. Duan Z. Wang H. Zhao L. Yu J. Ding Y. Wang S. Long noncoding RNA CRNDE stabilized by hnRNPUL2 accelerates cell proliferation and migration in colorectal carcinoma via activating Ras/MAPK signaling pathways.Cell Death Dis. 2017; 8: e2862Crossref PubMed Scopus (70) Google Scholar Upon binding of STAU1 to the SBS, the complex recruits UPF1 to the 3′ UTR of the target mRNA, thereby inducing mRNA degradation and shortening the half-life of target mRNA.21Kim M.Y. Park J. Lee J.J. Ha D.H. Kim J. Kim C.G. Hwang J. Kim C.G. Staufen1-mediated mRNA decay induces Requiem mRNA decay through binding of Staufen1 to the Requiem 3'UTR.Nucleic Acids Res. 2014; 42: 6999-7011Crossref PubMed Scopus (16) Google Scholar Therefore, we examined the potential influence of LINC00665 downregulation in glioma with STAU1 expression as a potential mechanism by which RNA dysfunction mediates malignancy. Metal regulatory transcription factor 1 (MTF1) is a highly conserved Cys2His2 zinc finger protein with six zinc finger domains, and it also plays a key role in transcriptional regulation by binding to DNA.22Kim S.K. Park Y.K. Ewing sarcoma: a chronicle of molecular pathogenesis.Hum. Pathol. 2016; 55: 91-100Crossref PubMed Scopus (31) Google Scholar,23Kim Y.K. Furic L. Desgroseillers L. Maquat L.E. Mammalian Staufen1 recruits Upf1 to specific mRNA 3'UTRs so as to elicit mRNA decay.Cell. 2005; 120: 195-208Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar MTF1 can be activated by growth factors, redox stress, and cytokines, thus playing a crucial role in both embryogenesis and hematopoiesis. Moreover, MTF1 has been shown to be overexpressed in breast cancer, cervical cancer, colorectal cancer, and lung cancer, suggesting a potential role in malignancy.22Kim S.K. Park Y.K. Ewing sarcoma: a chronicle of molecular pathogenesis.Hum. Pathol. 2016; 55: 91-100Crossref PubMed Scopus (31) Google Scholar,24Klar M. Fenske P. Vega F.R. Dame C. Bräuer A.U. Transcription factor Yin-Yang 2 alters neuronal outgrowth in vitro.Cell Tissue Res. 2015; 362: 453-460Crossref PubMed Scopus (8) Google Scholar We further focused on the potential role of the YY2 transcription factor (YY2) in glioma, as a multi-functional transcription factor of the YY family. As a paralog of YY1, YY2 has different modes of regulation on multiple tissues and cells, and it participates in the self-renewal and differentiation of mouse embryonic stem cells into cardiovascular lineages.25Köster T. Marondedze C. Meyer K. Staiger D. RNA-binding proteins revisited—the emerging arabidopsis mRNA interactome.Trends Plant Sci. 2017; 22: 512-526Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,26Kovar H. Dr. Jekyll and Mr. Hyde: the two faces of the FUS/EWS/TAF15 protein family.Sarcoma. 2011; 2011: 837474Crossref PubMed Scopus (89) Google Scholar Finally, we explored the influence of LINC00665 downregulation in glioma by examining its influence on microtubule-localized protein G2 and S-phase expressed 1 (GTSE1), which is expressed in the S and G2 phases of the cell cycle and is thus directly associated with carcinogenesis. Indeed, GTSE1 expression is upregulated in acral melanoma and gastric cancer.27Li S. Zhou J. Wang Z. Wang P. Gao X. Wang Y. Long noncoding RNA GAS5 suppresses triple negative breast cancer progression through inhibition of proliferation and invasion by competitively binding miR-196a-5p.Biomed. Pharmacother. 2018; 104: 451-457Crossref PubMed Scopus (96) Google Scholar,28Li, W., Zhao, W., Lu, Z., Zhang, W., and Yang, X. (201b). Long noncoding RNA GAS5 promotes proliferation, migration, and invasion by regulation of miR-301a in esophageal cancer. Oncol. Res. 26, 1285–1294.Google Scholar When facing DNA damage, GTSE1 accumulates and binds to p53, inhibiting its ability to induce apoptosis, suggesting its involvement in the p53 signaling pathway.29Lindén M. Thomsen C. Grundevik P. Jonasson E. Andersson D. Runnberg R. Dolatabadi S. Vannas C. Luna Santamarίa M. Fagman H. et al.FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex.EMBO Rep. 2019; 20: e45766Crossref PubMed Scopus (33) Google Scholar Our study first validated the expression of TAF15, LINC00665, MTF1, YY2, and GTSE1 in glioma. We further explored the potential mechanisms by which these factors interact and influence glioma malignant progression, focusing on the SMD process. These results can lay a new foundation for obtaining insights into the roles of lncRNAs and the underlying molecular mechanisms in glioma malignancy, and guide the development of innovative approaches for glioma treatment. As shown in Figures 1A and 1B , TAF15 expression was downregulated in both glioma tissues and cells. Moreover, high expression of TAF15 was negatively associated with poor prognosis in patients with glioma (Figure S1A). The microarray analysis results showed that the expression level of LINC00665 was decreased in U87 and U251 glioma cells compared to that in human astrocytes (Figure S2A). Similarly, LINC00665 expression was downregulated in glioma tissues compared with that in normal brain tissues (NBTs) and was negatively correlated with the pathological grade of glioma (Figure 1C). An RNA fluorescence in situ hybridization (FISH) assay was used to determine the subcellular location and expression of LINC00665, confirming decreased expression in U87 and U251 glioma cells compared with that in human astrocytes (Figures 1D and 1E). To verify the functions of TAF15 and LINC00665 in glioma cells, the impact on cell proliferation was assessed with the Cell Counting Kit-8 (CCK-8) assay, apoptosis was assessed with flow cytometry, and migration/invasion potential was assessed with transwell assays. As expected, upregulation of TAF15 and LINC00665 expression, respectively, inhibited the proliferation, migration, and invasion of glioma cells and promoted their apoptosis (Figures 1F–1H). Quantitative real-time PCR and microarray analysis showed that LINC00665 expression was upregulated in glioma cells with TAF15 overexpression (Figure 2A; Figure S2B). Furthermore, simultaneous overexpression of TAF15 and LINC00665 resulted in weaker proliferation, migration, and invasion capacity, as well as stronger induction of apoptosis, compared with overexpression of TAF15 or LINC00665 alone (Figures 1F–1H). starBase was used to predict the existence of the binding site between LINC00665 and TAF15 (Figure S1B), and their interaction was confirmed with RNA immunoprecipitation (RNA-IP) and RNA pull-down assays. As shown in Figure 2B, the enrichment of LINC00665 was significantly higher in the anti-TAF15 group compared with that in the anti-immunoglobulin G (IgG) group. The RNA pull-down assay also revealed that TAF15 could bind to LINC00665 (Figure 2C). Therefore, we hypothesized that LINC00665 was involved in the TAF15-mediated regulation of glioma cells. In exploring the mechanism in this regulation network, we found no significant difference of the nascent LINC00665 expression level between the TAF15 overexpression group and the NC group (Figure 2D). However, the half-life of LINC00665 was found to be significantly prolonged in the TAF15+ group compared with that in the TAF15+-negative control (NC) group (Figure 2E). These results confirmed that LINC00665 stabilized by TAF15 could inhibit the malignant progression of glioma cells. MTF1 expression was upregulated in both the glioma tissues and cells, and RNA FISH assays confirmed the high expression level of MTF1 in glioma cell lines (Figures 2F and 2G; Figure S2C). Moreover, high expression of MTF1 was positively associated with a poor prognosis in patients with glioma (Figure S1C). Compared with the NC group, the proliferation rate of glioma cells in the MTF1 overexpression group, MTF1+, was significantly higher, whereas that in the MTF1 knockdown group, MTF1−, was significantly decreased (Figure 2H). In addition, glioma cells in the MTF1+ group showed significantly lower rates of apoptosis, along with increased numbers of migrating and invading cells, whereas knockdown of MTF1 significantly promoted apoptosis with reduced migration and invasion capacity (Figures 2I and 2J). Interestingly, overexpression of LINC00665 depleted the expression of MTF1 at both the mRNA and protein levels, whereas knockdown of STAU1 significantly increased MTF1 expression and could partially rescue the LINC00665-induced reduction of MTF1 levels (Figures 3A and 3B ). To explore the mechanism of this LINC00665/MTF1 axis, an RNA-IP assay was used to verify the association among LINC00665, MTF1, and STAU1. The relative enrichment levels of LINC00665 and MTF1 were both significantly increased in the anti-STAU1 group compared to those in the anti-IgG group (Figure 3C). Furthermore, luciferase gene reporter assays were performed to clarify the association between LINC00665 and the MTF1 3′ UTR, and to identify the SBS. As shown in Figure 3D, the relative luciferase activity in the MTF1-3′ UTR-wild-type (WT) + LINC00665 group was significantly decreased compared with that in the NC group, whereas there was no such difference between the MTF1-3′ UTR-mutant-type (Mut) + LINC00665 and control groups. After treatment with actinomycin D, quantitative real-time PCR was used to compare the half-life of MTF1 mRNA in the two groups, showing a significantly shortened half-life in the LINC00665+ group and a prolonged half-life in the STAU1− group (Figures 3E and 3F). Considering the potential involvement of UPF1 in the SMD pathway, we also measured the half-life along with the mRNA and protein expression levels of MTF1 in glioma cells with UPF1 knockdown, demonstrating the expected results (Figures S3A–S3C). These results confirmed that LINC00665 destabilized MTF1 mRNA by forming a complex with STAU1 to recruit UPF1. Thus, we next investigated whether MTF1 could rescue the LINC00665-induced inhibition of the malignant progression of glioma cells. The LINC00665+ + MTF1− group showed a decreased proliferation rate, increased apoptosis rate, and reduced migration and invasion capacity compared with those of the LINC00665+ + MTF1+ group. In contrast, the LINC00665− + MTF1+ group showed significantly enhanced proliferation, migration, and invasion, with reduced apoptosis compared with those of the LINC00665− + MTF1− group (Figures 3G–3I). These results indicated that LINC00665 could inhibit the malignant behaviors of glioma cells via STAU1-mediated MTF1 mRNA degradation. Western blot and RNA FISH assays demonstrated that YY2 was upregulated in both glioma tissues and cells (Figures 4A and 4B ; Figure S2D). Moreover, high expression of YY2 was positively associated with poor prognosis in patients with glioma (Figure S1D). Glioma cells with YY2 overexpression also showed a significantly increased proliferation rate compared with that of the cells transfected with the NC vector (Figure 4C). Moreover, overexpression of YY2 significantly inhibited the apoptosis of glioma cells, whereas knockdown of YY2 promoted apoptosis (Figure 4D). Similarly, overexpression of YY2 significantly increased the numbers of migrating and invading glioma cells, which were reduced with YY2 knockdown (Figure 4E). Overexpression of LINC00665 in glioma cells resulted in downregulated expression of the transcription factor YY2. Furthermore, when STAU1 was knocked down in U87 and U251 glioma cells, YY2 expression was upregulated compared with that in the STAU1− NC group. Moreover, LINC00665 overexpression combined with STAU1 inhibition could rescue the reduction in MTF1 mRNA and protein expression levels compared with that in the LINC00665+ group (Figures 4F and 4G). Using the bioinformatics software RepeatMasker and IntaRNA, we analyzed the putative SBS between LINC00665 and YY2, and luciferase gene reporter assays were used to precisely identify the SBS to clarify the interaction between LINC00665 and the YY2 mRNA 3′ UTR (Figure 5A). An RNA-IP assay was used to further investigate the effect of the combination of LINC00665, YY2, and STAU1, showing that the relative enrichment of both LINC00665 and YY2 was significantly increased in the anti-STAU1 group compared to those in the anti-IgG group (Figure 5B). Moreover, compared with the LINC00665+-NC group, overexpression of LINC00665 could crucially reduce the half-life of YY2 (Figure 5E), whereas STAU1 or UPF1 inhibition in glioma cells could substantially extend the half-life of YY2 mRNA (Figure 5D; Figures S3D–S3F). Consistent with our hypothesis, the proliferation of glioma cells in the LINC00665+ + YY2− group was significantly decreased compared with that in the LINC00665+ + YY2+ group (Figure 5E). However, there was a higher ratio of apoptotic cells in the LINC00665+ + YY2− group compared with that in the LINC00665+ + YY2+ group (Figure 5F). Moreover, glioma cells in LINC00665− + YY2+ group showed increased migration and invasion rates compared with those in the LINC00665− + YY2− group (Figure 5G). These results clarified that LINC00665 also inhibited YY2 mRNA degradation through the SMD pathway to regulate the malignant behaviors of glioma cells. Compared with NBTs and human astrocytes, the expression level of GTSE1 in both glioma tissues and cells, respectively, was significantly increased (Figures 6A and 6B ). The Gene Expression Profiling Interactive Analaysis (GEPIA) database shows that GTSE1 is upregulated in glioblastoma and high expression of GTSE1 was positively associated with poor prognosis in patients with glioma (Figures S1E and S1F). Knockdown of GTSE1 inhibited glioma cell proliferation and promoted apoptosis compared with those in the GTSE1−-NC group (Figures 6C and 6D). Moreover, the numbers of migrating and invading cells was reduced in the GTSE1− group compared with those in the GTSE1-NC group (Figure 6E). We next evaluated the potential regulatory effect of MTF1 and YY2 on GTSE1. Western blot and quantitative real-time PCR showed that both MTF1 and YY2 overexpression increased the mRNA and protein expression levels of GTSE1, whereas simultaneous knockdown of MTF1 and YY2 reduced GTSE1 levels (Figures 6F–6I). The bioinformatics databases DataBase of Transcriptional Start Sites (DBTSS) and JASPAR were used to identify the putative binding site in the region 2,000 bp upstream of the GTSE1 transcription start site, indicating that MTF1 could directly bind to the GTSE1 promoter region through putative binding site 1, and this interaction was confirmed with a chromatin immunoprecipitation (ChIP) assay (Figure 7A). Since LINC00665 and MTF1 showed opposite functions in regulating the malignant progression of glioma, we hypothesized that downregulation of MTF1 expression might rescue the LINC00665-mediated reduction in GTSE1 expression. In line with this expectation, the LINC00665+ + MTF1− group showed stronger reductions in GTSE1 mRNA and protein expression levels compared with the LINC00665+ + MTF1+ group, and their expression levels were significantly higher in the LINC00665− + MTF1+ group than those in the LINC00665− + MTF1− group (Figures 7B and 7C). DBTSS and JASPAR indicated that the GTSE1 promoter contains three putative binding sites for YY2, and the ChIP assay showed that YY2 could directly bind to the GTSE1 promoter at putative binding sites 2 and 3, whereas there were no interactions observed in the NC or at putative binding site 1 (Figure 7D). Similarly, both GTSE1 mRNA and protein levels were decreased in the LINC00665+ + YY2− group compared with those of the LINC00665+ + YY2+ group, and the expression levels were higher in the latter group (Figures 7E and 7F). These results indicated that both MTF1 and YY2 participate in the transcriptional promotion of GTSE1. Furthermore, we verified that GTSE1 overexpression might rescue the LINC00665-mediated reduction in GTSE1 expression. In line with this expectation, the LINC00665+ + GTSE1+ group increased GTSE1 expression compared with the LINC00665+ + GTSE1+-NC group (Figure S4A). Additionally, the LINC00665+ + GTSE1+ group showed an increased proliferation rate, decreased apoptosis rate, and enhanced migration and invasion capacity compared with those of the LINC00665+ + GTSE1+-NC group (Figures S4B–S4D). Finally, we evaluated the influence of these four factors in vivo using a nude mice glioma xenograft model. As shown in Figure 8A, nude mice in the groups injected with TAF15+, LINC00665+, MTF1−, and YY2− glioma cells developed smaller tumors compared with those of the control group. Furthermore, the TAF15+ + LINC00665+ + MTF1− and TAF15+ + LINC00665++YY2− groups had the smallest tumor volumes overall (Figure 8B). The survival analysis indicated that mice in all of the treatment groups achieved longer survival than did those in the control group, although the nude mice in the TAF15+ + LINC00665+ + MTF1− and TAF15+ + LINC00665++YY2− groups showed the longest survival time (Figure 8C). Furthermore, we evaluated the influence of GTSE1 knockdown in vivo and found that nude mice in the groups injected with GTSE1− glioma cells developed smaller tumors and gained longer survival time than did those in the control group (Figures S5A–S5C). In this study, we identified the role of the TAF15/LINC00665/MTF1(YY2)/GTSE1 axis in the malignant progression of glioma, highlighting new targets for research and molecular therapy. TAF15 and LINC00665 were downregulated in glioma tissues and cells; moreover, TAF15 overexpression enhanced the stability of LINC00665, thus inhibiting the malignant progression of glioma cells. In contrast, the transcription factors MTF1 and YY2 were upregulated in glioma cells, and their knockdown, respectively, inhibited malignant progression. Mechanistically, overexpression of LINC00665 was confirmed to destabilize MTF1 and YY2 mRNAs by interacting with STAU1. In line with this mechanism, depletion of STAU1 could rescue the MTF1 and YY2 mRNA degradation caused by LINC00665 overexpression. GTSE1 was upregulated in glioma. However, knockdown of MTF1 or YY2 decreased the mRNA and protein expression levels of GTSE1 through direct binding to its promoter region, thus repressing proliferation, migration, and invasion and promoting the apoptosis of glioma cells. A schematic of the proposed mechanisms driven by this axis is provided in Figure 8D. TAF15 belongs to the FET family of conserved RBPs that play essential roles in the tumorigenesis of various cancers such as liposarcoma and neuroectodermal tumor.30Liu A. Zeng S. Lu X. Xiong Q. Xue Y. Tong L. Xu W. Sun Y. Zhang Z. Xu C. Overexpression of G2 and S phase-expressed-1 contributes to cell proliferation, migration, and invasion via regulating p53/FoxM1/CCNB1 pathway and predicts poor prognosis in bladder cancer.Int." @default.
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• W3022019982 date "2020-06-01" @default.
• W3022019982 modified "2023-10-16" @default.
• W3022019982 title "lncRNA LINC00665 Stabilized by TAF15 Impeded the Malignant Biological Behaviors of Glioma Cells via STAU1-Mediated mRNA Degradation" @default.
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• W3022019982 doi "https://doi.org/10.1016/j.omtn.2020.05.003" @default.
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