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

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

Authors :
Ulvi Ahmadov
Daniel Picard
Jasmin Bartl
Manuela Silginer
Marija Trajkovic-Arsic
Nan Qin
Lena Blümel
Marietta Wolter
Jonathan K. M. Lim
David Pauck
Alina Marie Winkelkotte
Marlen Melcher
Maike Langini
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 Leprivier
Kai Stühler
Simone Fulda
Jens T. Siveke
Felix Distelmaier
Arndt Borkhardt
Michael Weller
Patrick Roth
Guido Reifenberger
Marc Remke
Source :
Cell Death and Disease, Vol 12, Iss 10, Pp 1-11 (2021)
Publication Year :
2021
Publisher :
Nature Publishing Group, 2021.

Abstract

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.

Subjects

Subjects :
Cytology
QH573-671

Details

Language :
English
ISSN :
20414889
Volume :
12
Issue :
10
Database :
Directory of Open Access Journals
Journal :
Cell Death and Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.7af56daa21a545719f08c431620aa3e9
Document Type :
article
Full Text :
https://doi.org/10.1038/s41419-021-04146-0