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Abstract
Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
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1 German Cancer Research Center (DKFZ), Division of Pediatric Neuro-Oncogenomics, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); German Consortium for Translational Cancer Research (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany (GRID:grid.7497.d); University Hospital Düsseldorf, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Düsseldorf, Germany (GRID:grid.14778.3d) (ISNI:0000 0000 8922 7789); Heinrich Heine University, Department of Neuropathology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917)
2 University Hospital and University of Zurich, Department of Neurology, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650)
3 University Medicine Essen, Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, Essen, Germany (GRID:grid.7400.3); Division of Solid Tumor Translational Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), partner site Essen, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584)
4 Heinrich Heine University, Department of Neuropathology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917)
5 University Medicine Essen, Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, Essen, Germany (GRID:grid.411327.2); Division of Solid Tumor Translational Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), partner site Essen, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584)
6 University Hospital Düsseldorf, Department of General Pediatrics, Neonatology and Pediatric Cardiology, Düsseldorf, Germany (GRID:grid.14778.3d) (ISNI:0000 0000 8922 7789)
7 Heinrich Heine University, Institute for Molecular Medicine I, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917); Heinrich Heine University, Molecular Proteomics Laboratory (MPL), Biological-Medical Research Center (BMFZ), Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917)
8 University Hospital Essen, Department of Molecular Oncology, West German Cancer Center, Essen, Germany (GRID:grid.410718.b) (ISNI:0000 0001 0262 7331)
9 Goethe University Frankfurt, Institute for Experimental Cancer Research in Pediatrics, Frankfurt, Germany (GRID:grid.7839.5) (ISNI:0000 0004 1936 9721); Partner Site Frankfurt and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584)
10 Heinrich Heine University, Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917)
11 University Hospital Düsseldorf, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Düsseldorf, Germany (GRID:grid.14778.3d) (ISNI:0000 0000 8922 7789)
12 University Medicine Essen, Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, Essen, Germany (GRID:grid.7497.d); Division of Solid Tumor Translational Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), partner site Essen, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584)
13 German Cancer Research Center (DKFZ), Division of Pediatric Neuro-Oncogenomics, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); German Consortium for Translational Cancer Research (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany (GRID:grid.7497.d); University Hospital Düsseldorf, Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, Düsseldorf, Germany (GRID:grid.14778.3d) (ISNI:0000 0000 8922 7789)
14 German Cancer Research Center (DKFZ), Division of Pediatric Neuro-Oncogenomics, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); German Consortium for Translational Cancer Research (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany (GRID:grid.7497.d); Heinrich Heine University, Department of Neuropathology, Medical Faculty, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917)