The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma

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 co...

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Published in:	Cell death & disease Vol. 12; no. 10; pp. 885 - 11
Main Authors:	Ahmadov, Ulvi, Picard, Daniel, Bartl, Jasmin, Silginer, Manuela, Trajkovic-Arsic, Marija, Qin, Nan, Blümel, Lena, Wolter, Marietta, Lim, Jonathan K. M., Pauck, David, Winkelkotte, Alina Marie, Melcher, Marlen, Langini, Maike, Marquardt, Viktoria, Sander, Felix, Stefanski, Anja, Steltgens, Sascha, Hassiepen, Christina, Kaufhold, Anna, Meyer, Frauke-Dorothee, Seibt, Annette, Kleinesudeik, Lara, Hain, Anika, Münk, Carsten, Knobbe-Thomsen, Christiane Brigitte, Schramm, Alexander, Fischer, Ute, Leprivier, Gabriel, Stühler, Kai, Fulda, Simone, Siveke, Jens T., Distelmaier, Felix, Borkhardt, Arndt, Weller, Michael, Roth, Patrick, Reifenberger, Guido, Remke, Marc
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 28-09-2021 Springer Nature B.V Nature Publishing Group
Subjects:	13/106 13/109 38/109 38/39 38/89 38/90 38/91 631/337/2019 631/337/384/2568 631/337/475 631/67/69 64/60 82/58 Animals Antibodies Antisense RNA Biochemistry Biomarkers Biomedical and Life Sciences Brain cancer Brain tumors Carcinogenesis - genetics Carcinogenesis - pathology Cell Biology Cell Culture Cell Line, Tumor Cell Survival - genetics Cell viability Clone Cells DNA methylation DNA methyltransferase Down-Regulation - genetics Gene expression Gene Expression Regulation, Neoplastic Glioblastoma Glioblastoma - genetics Glioblastoma - pathology Glioblastoma - radiotherapy Glioblastoma cells Humans Immunology Isocitrate dehydrogenase Life Sciences Medical prognosis Methylguanine Mice Mice, Nude MicroRNAs - genetics MicroRNAs - metabolism Mitochondria Mitochondria - metabolism Mutation Neoplasm Invasiveness Non-coding RNA O6-methylguanine-DNA methyltransferase Phenotype Phenotypes Prognosis Protein Glutamine gamma Glutamyltransferase 2 - metabolism Proteogenomics Radiation therapy Radiation Tolerance - genetics Radioresistance Radiosensitivity Reactive oxygen species Reactive Oxygen Species - metabolism RNA, Small Interfering - metabolism Transcription Transglutaminase 2
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Summary:	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.
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-021-04146-0