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The lncRNA HOTAIR has been implicated in several human cancers. Here, weevaluated the molecular alterations and upstream regulatory mechanisms ofHOTAIR in glioma, the most common primary brain tumors, and its clinicalrelevance. HOTAIR gene expression, methylation, copy-number and prognosticvalue were investigated in human gliomas integrating data from online datasetsand our cohorts. High levels of HOTAIR were associated with higher grades ofglioma, particularly IDH wild-type cases. Mechanistically, HOTAIR wasoverexpressed in a gene dosage-independent manner, while DNA methylation levelsof particular CpGs in HOTAIR locus were associated with HOTAIR expressionlevels in GBM clinical specimens and cell lines. Concordantly, thedemethylating agent 5-Aza-2'-deoxycytidine affected HOTAIR transcriptionallevels in a cell line-dependent manner. Importantly, HOTAIR was frequentlyco-expressed with HOXA9 in high-grade gliomas from TCGA, Oncomine, and ourPortuguese and French datasets. Integrated in silico analyses, chromatinimmunoprecipitation, and qPCR data showed that HOXA9 binds directly to thepromoter of HOTAIR. Clinically, GBM patients with high HOTAIR expression had asignificantly reduced overall survival, independently of other prognosticvariables. In summary, this work reveals HOXA9 as a novel direct regulator ofHOTAIR, and establishes HOTAIR as an independent prognostic marker, providingnew therapeutic opportunities to treat this highly aggressive cancer.

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