The long non-coding RNA HOTAIR is transcriptionally activated by HOXA9 and is an independent prognostic marker in patients with malignant glioma

• Published in: Oncotarget Vol. 9; no. 21; pp. 15740 - 15756
• Main Authors: Xavier-Magalhães, Ana, Gonçalves, Céline S, Fogli, Anne, Lourenço, Tatiana, Pojo, Marta, Pereira, Bruno, Rocha, Miguel, Lopes, Maria Celeste, Crespo, Inês, Rebelo, Olinda, Tão, Herminio, Lima, João, Moreira, Ricardo, Pinto, Afonso A, Jones, Chris, Reis, Rui M, Costello, Joseph F, Arnaud, Philippe, Sousa, Nuno, Costa, Bruno M
• Format: Journal Article
• Language: English
• Published: United States Impact journals 20.03.2018; Impact Journals LLC
• Subjects: Biochemistry, Molecular Biology; Cancer; Genomics; Life Sciences; Molecular biology; Molecular Networks; Research Paper; HOTAIR; glioma; HOXA9; glioblastoma; prognosis
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.24597

The lncRNA has been implicated in several human cancers. Here, we evaluated the molecular alterations and upstream regulatory mechanisms of in glioma, the most common primary brain tumors, and its clinical relevance. gene expression, methylation, copy-number and prognostic value were investigated in human gliomas integrating data from online datasets and our cohorts. High levels of were associated with higher grades of glioma, particularly IDH wild-type cases. Mechanistically, was overexpressed in a gene dosage-independent manner, while DNA methylation levels of particular CpGs in locus were associated with expression levels in GBM clinical specimens and cell lines. Concordantly, the demethylating agent 5-Aza-2'-deoxycytidine affected transcriptional levels in a cell line-dependent manner. Importantly, was frequently co-expressed with in high-grade gliomas from TCGA, Oncomine, and our Portuguese and French datasets. Integrated analyses, chromatin immunoprecipitation, and qPCR data showed that HOXA9 binds directly to the promoter of . Clinically, GBM patients with high expression had a significantly reduced overall survival, independently of other prognostic variables. In summary, this work reveals as a novel direct regulator of , and establishes as an independent prognostic marker, providing new therapeutic opportunities to treat this highly aggressive cancer.