Produção Nacional
The long non-coding RNA HOTAIR is transcriptionally activated by HOXA9 and is an independent prognostic marker in patients with malignant glioma
2018; Impact Journals LLC; Volume: 9; Issue: 21 Linguagem: Inglês
10.18632/oncotarget.24597
ISSN1949-2553
AutoresAna Xavier‐Magalhães, Céline S. Gonçalves, Anne Fogli, Tatiana Lourenço, Marta Pojo, Bruno Pereira, Miguel Rocha, M Lopes, Inês Crespo, Olinda Rebelo, Herminio Tão, João Lima, Ricardo Moreira, Afonso A. Pinto, Chris Jones, Rui Manuel Reis, Joseph F. Costello, Philippe Arnaúd, Nuno Sousa, Bruno M. Costa,
Tópico(s)RNA Research and Splicing
Resumo// Ana Xavier-Magalhães 1, 2, * , Céline S. Gonçalves 1, 2, * , Anne Fogli 3, 4 , Tatiana Lourenço 1, 2 , Marta Pojo 1, 2 , Bruno Pereira 5 , Miguel Rocha 6 , Maria Celeste Lopes 7 , Inês Crespo 7 , Olinda Rebelo 7 , Herminio Tão 7 , João Lima 8 , Ricardo Moreira 8 , Afonso A. Pinto 8 , Chris Jones 9 , Rui M. Reis 1, 2, 10 , Joseph F. Costello 11 , Philippe Arnaud 3 , Nuno Sousa 1, 2 and Bruno M. Costa 1, 2 1 Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal 2 ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimarães, Braga, Portugal 3 GReD, Université Clermont Auvergne, CNRS, INSERM, Clermont-Ferrand, France 4 Biochemistry and Molecular Biology Department, Clermont-Ferrand Hospital, Clermont-Ferrand, France 5 Biostatistics Department, DRCI, Clermont-Ferrand Hospital, Clermont-Ferrand, France 6 Centre of Biological Engineering, School of Engineering, University of Minho, Campus de Gualtar, Braga, Portugal 7 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal 8 Department of Neurosurgery, Hospital Escala Braga, Braga, Portugal 9 Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom 10 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil 11 Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA * These authors contributed equally to this work Correspondence to: Bruno M. Costa, email: bfmcosta@med.uminho.pt Keywords: HOTAIR; glioblastoma; glioma; prognosis; HOXA9 Received: October 19, 2017 Accepted: February 21, 2018 Epub: February 28, 2018 Published: March 20, 2018 ABSTRACT The lncRNA HOTAIR has been implicated in several human cancers. Here, we evaluated the molecular alterations and upstream regulatory mechanisms of HOTAIR in glioma, the most common primary brain tumors, and its clinical relevance. HOTAIR gene expression, methylation, copy-number and prognostic value were investigated in human gliomas integrating data from online datasets and our cohorts. High levels of HOTAIR were associated with higher grades of glioma, particularly IDH wild-type cases. Mechanistically, HOTAIR was overexpressed in a gene dosage-independent manner, while DNA methylation levels of particular CpGs in HOTAIR locus were associated with HOTAIR expression levels in GBM clinical specimens and cell lines. Concordantly, the demethylating agent 5-Aza-2′-deoxycytidine affected HOTAIR transcriptional levels in a cell line-dependent manner. Importantly, HOTAIR was frequently co-expressed with HOXA9 in high-grade gliomas from TCGA, Oncomine, and our Portuguese and French datasets. Integrated in silico analyses, chromatin immunoprecipitation, and qPCR data showed that HOXA9 binds directly to the promoter of HOTAIR . Clinically, GBM patients with high HOTAIR expression had a significantly reduced overall survival, independently of other prognostic variables. In summary, this work reveals HOXA9 as a novel direct regulator of HOTAIR , and establishes HOTAIR as an independent prognostic marker, providing new therapeutic opportunities to treat this highly aggressive cancer.
Referência(s)