title: C/EBPα-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia.
abstract: Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-α (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPα occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPα-p30. We show that wild-type C/EBPα and C/EBPα-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPα represses, C/EBPα-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPα in AML.
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors.forename: James M
authors.initials: JM
authors.lastname: Hughes
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Legnini
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.|Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Salvatori
authors.affiliation: Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Masciarelli
authors.affiliation: Institute of Biology, Molecular Medicine and Nanobiotechnology, CNR, Sapienza University of Rome, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Marchioni
authors.affiliation: Department of Anatomical, Histological, Forensic & Orthopaedic Sciences, Sapienza University of Rome, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazi
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Morlando
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.|Institute of Biology, Molecular Medicine and Nanobiotechnology, CNR, Sapienza University of Rome, Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.|Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
authors.affiliation: Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatica
mesh_terms: D000208:Acute Disease; D014408:Biomarkers, Tumor / Q000235:genetics; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015151:Immunoblotting; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D022763:CCAAT-Enhancer-Binding Protein-alpha; C436291:CDKN1B protein, human; D020033:Protein Isoforms; D062085:RNA, Long Noncoding; C515159:UCA1 RNA, human; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: CEBPA; UCA1; acute myeloid leukemia; long non-coding RNA