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 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.
Metadaten
Author:Ulvi AhmadovORCiDGND, Daniel Picard, Jasmin BartlORCiDGND, Manuela Silginer, Marija Trajkovic-Arsic, Nan Qin, Lena Blümel, Marietta Wolter, Jonathan K. M. Lim, David Pauck, Alina M. Winkelkotte, Marlen Melcher, Maike LanginiORCiDGND, Viktoria Marquardt, Felix Sander, Anja Stefanski, Sascha Steltgens, Christina Hassiepen, Anna Kaufhold, Frauke-Dorothee Meyer, Annette Seibt, Lara Kleinesudeik, Anika Hain, Carsten Münk, Christiane Brigitte Knobbe-Thomsen, Alexander Schramm, Ute Fischer, Gabriel LeprivierORCiDGND, Kai Stühler, Simone FuldaORCiDGND, Jens SivekeORCiDGND, Felix Distelmaier, Arndt BorkhardtORCiDGND, Michael WellerORCiDGND, Patrick Roth, Guido Reifenberger, Marc Remke
URN:urn:nbn:de:hebis:30:3-644919
DOI:https://doi.org/10.1038/s41419-021-04146-0
ISSN:2041-4889
Parent Title (English):Cell death & disease
Publisher:Nature Publishing Group
Place of publication:London [u.a.]
Document Type:Article
Language:English
Date of Publication (online):2021/09/28
Date of first Publication:2021/09/28
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/03/14
Tag:Cancer genomics; Long non-coding RNAs; Proteomics; Transcriptomics
Volume:12
Issue:art. 885
Page Number:11
First Page:1
Last Page:11
Note:
This project was supported by a joint grant from the Deutsche Forschungsgemeinschaft (German Research Foundation) and the Swiss National Science Foundation to M.R., G.R., P.R., and M.W. (RE2857/2-1, RE938/4-1; SNF 310030E_170717). This work was also partly supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) [RE2857/4-1, SCHE 656/2-1 (KFO 337)]. J.T.S. is supported by the German Cancer Consortium (DKTK), the Deutsche Forschungsgemeinschaft (DFG) grant SI1549/3-1 (DFG/GRC-CRU337) and SI1549/4-1, and the German Cancer Aid (Grant no. 70112505; PIPAC consortium). Open Access funding enabled and organized by Projekt DEAL.
HeBIS-PPN:494331917
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0