Dataset Information

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

ABSTRACT: Glioblastoma is the most common malignant primary brain tumor. Clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutation and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNA (lncRNA) alterations may contribute to glioblastoma pathogenesis and potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was analyzed in multiple glioblastoma gene expression data sets for associations with prognosis and IDH mutation and MGMT promoter methylation status. 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, less invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses and determination of reactive oxygen species (ROS) levels revealed impaired mitochondrial function and increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2) as 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 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Glioblastoma

SUBMITTER: Anja Stefanski

LAB HEAD: Kai Stühler

PROVIDER: PXD020141 | Pride | 2022-01-19

REPOSITORIES: Pride

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Publications

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

Ahmadov Ulvi U Picard Daniel D Bartl Jasmin J Silginer Manuela M Trajkovic-Arsic Marija M Qin Nan N Blümel Lena L Wolter Marietta M Lim Jonathan K M JKM Pauck David D Winkelkotte Alina Marie AM Melcher Marlen M Langini Maike M Marquardt Viktoria V Sander Felix F Stefanski Anja A Steltgens Sascha S Hassiepen Christina C Kaufhold Anna A Meyer Frauke-Dorothee FD Seibt Annette A Kleinesudeik Lara L Hain Anika A Münk Carsten C Knobbe-Thomsen Christiane Brigitte CB Schramm Alexander A Fischer Ute U Leprivier Gabriel G Stühler Kai K Fulda Simone S Siveke Jens T JT Distelmaier Felix F Borkhardt Arndt A Weller Michael M Roth Patrick P Reifenberger Guido G Remke Marc M

Cell death & disease 20210928 10

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 analyzi ...[more]

PMID: 34584066

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Project description:This SuperSeries is composed of the SubSeries listed below. BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to the subgroup of methylguanin-O6-methyltransferase promoter (MGMT) hypermethylated tumors. Further resistance markers and pathways against chemotherapy and radiotherapy are largely unknown and would help for better stratification. METHODS: The diagnostic cohorts involved clinical data and methylation profiles of the NOA-08 (n = 104, elderly glioblastoma) and the EORTC 26101 (n = 297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg center. Twenty-eight glioblastoma CpGs from 17 DNA damage response (DDR) genes that negatively correlate with expression derived from a 450 DDR gene list as well as telomerase reverse transcriptase (TERT) promoter mutations were investigated for outcome and interaction with therapy and classifier assignments. RESULTS: CpG methylation in IDH wildtype tumors had the highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) I glioblastoma subgroup. MES tumors have lower tumor purity and differ in copy number variations on chromosomes 7 and 10 from the RTK I and II subtypes. CpG hypomethylation of DDR genes (TP73, CCND3, CSNK1E, EXO1, CUL4A and PRPF19) correlated with worse patient survival in particular in MGMT unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival in primary glioblastoma. Primary glioma cells show methylation pattern that resemble RTK I and II glioma and differ from long term established cell lines. Knock-down of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide treatment in vitro. CONCLUSION: Methylation of DDR genes and TERT promoter mutations are associated with tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in high-grade glioma.

Dataset Information

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

Publications

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

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