P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression.
Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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EB
Zhang
Central Laboratory, Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu, China.
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DD
Yin
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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M
Sun
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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R
Kong
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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XH
Liu
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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You
Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Han
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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Xia
Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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KM
Wang
Department of Oncology, Affiliated Nanjing Hospital of Nanjing Medical Univeraity, Nanjing, Jiangsu, China.
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JS
Yang
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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De
Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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YQ
Shu
Department of Oncology, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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ZX
Wang
D000818:Animals; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008745:Methylation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C490538:HOXB7 protein, human; D006657:Histones; D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2