HOTAIR is a therapeutic target in glioblastoma.

Xuan Zhou,Lei Han,Lingping Kong,Yuqi Yang,Tao Jiang,Min Li,Qixue Wang,Chunsheng Kang,Jianwei Wei,Luyue Chen,Jingxuan Yang,Yu Ren,Kailiang Zhang,Jing Zhang,Chuanbao Zhang,Jianning Zhang

doi:10.18632/oncotarget.3229

Abstract

HOTAIR is a negative prognostic factor and is overexpressed in multiple human cancers including glioblastoma multiform (GBM). Survival analysis of Chinese Glioma Genome Atlas (CGGA) patient data indicated that high HOTAIR expression was associated with poor outcome in GBM patients. NLK (Nemo-like kinase), a negative regulator of the β-catenin pathway, was negatively correlated with HOTAIR expression. When the β-catenin pathway was inhibited, GBM cells became susceptible to cell cycle arrest and inhibition of invasion. Introduction of the HOTAIR 5' domain in human glioma-derived astrocytoma induced β-catenin. An intracranial animal model was used to confirm that HOTAIR depletion inhibited GBM cell migration/invasion. In the orthotopic model, HOTAIR was required for GBM formation in vivo. In summary, HOTAIR is a potential therapeutic target in GBM.

Highlights

Glioblastoma multiform (GBM) is the most malignant tumor of the human central nervous system
HOTAIR interacts with another chromatin complex, the lysine-specific demethylase 1 (LSD1)-CoREST complex, which mediates the removal of mono- and di-methylation of H3K4, a histone mark associated with gene activation, in nucleosomes [11,12,13]
The HOTAIR gene is located within the HOXC gene cluster on chromosome 12 and encodes a 2.2 kb lincRNA molecule that repressed transcription in the more distal HOXD locus in foreskin fibroblasts [35]

Summary

Introduction

Glioblastoma multiform (GBM) is the most malignant tumor of the human central nervous system. Amplification of the EGFR gene, with the subsequent overexpression of the EGFR protein, is the most common genetic alteration in GBM, occurring at a frequency of approximately 34–63% [4, 5]. Aberrant signaling of EGFRvIII (the most common extracellular mutation) has been shown to be important in driving tumor progression and often correlates with poor prognosis for GBM patients [6, 7]. HOTAIR regulates the transcriptional silencing of genes of the HOXD locus and other genetic loci by binding to Polycomb repressive complex 2 (PRC2) (EZH2, SUZ12 and EED) at its 5’ end and localizing it to the specific site where H3K27 trimethylation and epigenetic silencing of gene expression occur [10]. HOTAIR interacts with another chromatin complex, the lysine-specific demethylase 1 (LSD1)-CoREST complex, which mediates the removal of mono- and di-methylation of H3K4, a histone mark associated with gene activation, in nucleosomes [11,12,13]

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