title: HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling.
abstract: It is well accepted that HBx plays the major role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. However, little was known about its role in regulating long noncoding RNAs (lncRNAs), a large group of transcripts regulating a variety of biological processes including carcinogenesis in mammalian cells. Here we report that HBx upregulates UCA1 genes and downregulates p27 genes in hepatic LO2 cells. Further studies show that the upregulated UCA1 promotes cell growth by facilitating G1/S transition through CDK2 in both hepatic and hepatoma cells. Knock down of UCA1 in HBx-expressing hepatic and hepatoma cells resulted in markedly increased apoptotic cells by elevating the cleaved caspase-3 and caspase-8. More importantly, UCA1 is found to be physically associated with enhancer of zeste homolog 2 (EZH2), which suppresses p27Kip1 through histone methylation (H3K27me3) on p27Kip1 promoter. We also show that knockdown of UCA1 in hepatoma cells inhibits tumorigenesis in nude mice. In a clinic study, UCA1 is found to be frequently up-regulated in HBx positive group tissues in comparison with the HBx negative group, and exhibits an inverse correlation between UCA1 and p27Kip1 levels. Our findings demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-UCA1/EZH2-p27Kip1 axis, and a potential target of HCC.
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Jiao-Jiao
authors.initials: JJ
authors.lastname: Hu
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Shao-Dan
authors.initials: SD
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Shen
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Qiu
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Hua-Zhang
authors.initials: HZ
authors.lastname: Wu
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Pi-Hai
authors.initials: PH
authors.lastname: Gong
authors.affiliation: The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Zhu-Jiang
authors.initials: ZJ
authors.lastname: Zhao
authors.affiliation: CUHK Shenzhen Research Institute, Shenzhen, China.|Department of Biomedical Sciences, City University of Hong Kong, Hong Kong.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: He
authors.affiliation: Department of Medical Genetics and Developmental Biology, Medical School of Southeast University, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Fan
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D049109:Cell Proliferation; D002472:Cell Transformation, Viral / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D062085:RNA, Long Noncoding / Q000235:genetics*; D012697:Serine Endopeptidases; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C436291:CDKN1B protein, human; D008565:Membrane Proteins; D062085:RNA, Long Noncoding; D015534:Trans-Activators; C515159:UCA1 RNA, human; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D012697:Serine Endopeptidases; C026515:type I signal peptidase