TY  - JOUR
A1  - Ahmadov, Ulvi
A1  - Picard, Daniel
A1  - Bartl, Jasmin
A1  - Silginer, Manuela
A1  - Trajkovic-Arsic, Marija
A1  - Qin, Nan
A1  - Blümel, Lena
A1  - Wolter, Marietta
A1  - Lim, Jonathan K. M.
A1  - Pauck, David
A1  - Winkelkotte, Alina M.
A1  - Melcher, Marlen
A1  - Langini, Maike
A1  - Marquardt, Viktoria
A1  - Sander, Felix
A1  - Stefanski, Anja
A1  - Steltgens, Sascha
A1  - Hassiepen, Christina
A1  - Kaufhold, Anna
A1  - Meyer, Frauke-Dorothee
A1  - Seibt, Annette
A1  - Kleinesudeik, Lara
A1  - Hain, Anika
A1  - Münk, Carsten
A1  - Knobbe-Thomsen, Christiane Brigitte
A1  - Schramm, Alexander
A1  - Fischer, Ute
A1  - Leprivier, Gabriel
A1  - Stühler, Kai
A1  - Fulda, Simone
A1  - Siveke, Jens
A1  - Distelmaier, Felix
A1  - Borkhardt, Arndt
A1  - Weller, Michael
A1  - Roth, Patrick
A1  - Reifenberger, Guido
A1  - Remke, Marc
T1  - The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma
T2  - Cell death & disease
N2  - 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.
KW  - Cancer genomics
KW  - Long non-coding RNAs
KW  - Proteomics
KW  - Transcriptomics
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/64491
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-644919
SN  - 2041-4889
N1  - 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.
VL  - 12
IS  - art. 885
SP  - 1
EP  - 11
PB  - Nature Publishing Group
CY  - London [u.a.]
ER  -