The long non-coding RNA HOTAIR is transcriptionally activated by HOXA9 and is an independent prognostic marker in patients with malignant glioma
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Ana Xavier-Magalhães1,2,*, Céline S. Gonçalves1,2,*, Anne Fogli3,4, Tatiana Lourenço1,2, Marta Pojo1,2, Bruno Pereira5, Miguel Rocha6, Maria Celeste Lopes7, Inês Crespo7, Olinda Rebelo7, Herminio Tão7, João Lima8, Ricardo Moreira8, Afonso A. Pinto8, Chris Jones9, Rui M. Reis1,2,10, Joseph F. Costello11, Philippe Arnaud3, Nuno Sousa1,2 and Bruno M. Costa1,2
1Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
2ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimarães, Braga, Portugal
3GReD, Université Clermont Auvergne, CNRS, INSERM, Clermont-Ferrand, France
4Biochemistry and Molecular Biology Department, Clermont-Ferrand Hospital, Clermont-Ferrand, France
5Biostatistics Department, DRCI, Clermont-Ferrand Hospital, Clermont-Ferrand, France
6Centre of Biological Engineering, School of Engineering, University of Minho, Campus de Gualtar, Braga, Portugal
7Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
8Department of Neurosurgery, Hospital Escala Braga, Braga, Portugal
9Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
10Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
11Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
*These authors contributed equally to this work
Bruno M. Costa, email: [email protected]
Keywords: HOTAIR; glioblastoma; glioma; prognosis; HOXA9
Received: October 19, 2017 Accepted: February 21, 2018 Epub: February 28, 2018 Published: March 20, 2018
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.
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