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

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.

Immunotherapy and Epigenetic Pathway Modulation in Glioblastoma Multiforme

“…The result of the study demonstrated that not only is HOTAIR dysregulated and that the dysregulated lncRNA facilitates GBM proliferation, but that there are also higher levels of HOTAIR in serum exosomes of GBM patients ( 52 ). This association between HOTAIR and GBM proliferation and expansion has been demonstrated by others as well in GBM patients in vivo ( 58 ). Additionally, it was discovered that HOTAIR mediates the ability of GBM cells to migrate and invade through membranes in vitro ( 56 ).…”

“…We and others determined whether HOTAIR levels were significantly correlated with GBM tumors and GBM serum ( 52 , 54 , 58 ). Quantitative real-time-PCR (qRT-PCR) was conducted to detect HOTAIR levels in 15 pairs of GBM tissue and GBM serum samples.…”

“…Additionally, it was discovered that HOTAIR mediates the ability of GBM cells to migrate and invade through membranes in vitro ( 56 ). Therefore, there is considerable evidence that not only is HOTAIR related to cancer proliferation, but that it is also an independent negative prognostic marker in GBM ( 54 , 58 ).…”

Potential of long non-coding RNAs as a therapeutic target and molecular markers in glioblastoma pathogenesis

“…In their study, they found that the co-expression of HOTAIR and HOXA9 (Homeobox A9) occurs frequently in glioblastoma condition that is regulated by the Phosphoinositide 3-kinases (PI3K) signaling pathway via inhibition of EZH2 (enhancer of zeste homolog 2)-mediated H3K27 trimethylation. In sum, they concluded that HOXA9 was a novel direct regulator of HOTAIR and established HOTAIR as an independent prognostic marker [ 88 ]. All of these findings suggest that HOTAIR expression initiates and facilitates GB growth and development via a variety of regulatory signals.…”

Coding of Glioblastoma Progression and Therapy Resistance through Long Noncoding RNAs

“…It promotes the invasion of gliomas through upregulation of the expression of matrix metalloproteinase-7 (MMP-7), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF) [76]. Integrated in silico analysis, chromatin immunoprecipitation, and quantitative PCR data have shown that homeobox A9 (HOXA9) binds directly to the promoter of HOTAIR and might serve as a novel direct regulator of HOTAIR [77]. Inhibition of HOTAIR in an in vivo xenograft mouse model slowed tumor growth, and prolonged the survival of the mice [78].…”