TP73-AS1 Promotes Chemotherapy resistance in Glioblatoma cancer stem cells

Glioblastoma multiform (GBM) is the most common brain tumour characterized by a dismal prognosis. GBM cancer stem cells (gCSC) or tumour-initiating cells are the cell population within the tumour driving therapy resistance and recurrence. While temozolomide (TMZ), an alkylating agent, constitutes the first-line chemotherapeutic significantly improving survival in GBM patients, resistance against this compound commonly leads to GBM recurrence and treatment failure. Although the roles of protein-coding transcripts, proteins and microRNA in gCSC and therapy resistance have been comprehensively investigated, very little is known about the role of long non-coding RNAs (lncRNAs) in this context. Using non-overlapping, independent RNA sequencing and gene expression profiling datasets, we reveal that TP73-AS1 constitutes a clinically-relevant lncRNA in GBM. Specifically, we demonstrate significant overexpression of TP73-AS1 in primary GBM samples, which is particularly increased in the gCSC. More importantly, we demonstrate that TP73-AS1 comprises a prognostic biomarker in glioma and in GBM with high expression identifying patients with particularly poor prognosis. Using CRISPRi to downregulate our candidate lncRNA in gCSC, we demonstrate that TP73-AS1 promotes TMZ resistance in gCSC and is linked to regulation of expression of metabolism related genes and ALDH1A1, a protein known to be expressed in cancer stem cell marker and protect gCSC from TMZ treatment. Taken together, our results reveal that high TP73-AS1 predicts poor prognosis in primary GBM cohorts and that this lncRNA promotes tumour aggressiveness and TMZ resistance in gCSC.