The lncRNA TP73-AS1 is linked to aggressiveness in glioblastoma and promotes temozolomide resistance in glioblastoma cancer stem cells

Cell Death Dis. 2019 Mar 13;10(3):246. doi: 10.1038/s41419-019-1477-5.

Abstract

Glioblastoma multiform (GBM) is the most common brain tumor characterized by a dismal prognosis. GBM cancer stem cells (gCSC) or tumor-initiating cells are the cell population within the tumor-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 noncoding RNAs (lncRNAs) in this context. Using nonoverlapping, 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 the expression of metabolism- related genes and ALDH1A1, a protein known to be expressed in cancer stem cell markers and protects 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 tumor aggressiveness and TMZ resistance in gCSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1 Family / genetics
  • Aldehyde Dehydrogenase 1 Family / metabolism
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Ontology
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • HEK293 Cells
  • Humans
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism*
  • Prognosis
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA-Seq
  • Retinal Dehydrogenase / genetics
  • Retinal Dehydrogenase / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Temozolomide / pharmacology*
  • Tumor Protein p73 / genetics
  • Tumor Protein p73 / metabolism

Substances

  • Antineoplastic Agents, Alkylating
  • Biomarkers, Tumor
  • RNA, Long Noncoding
  • TP73 protein, human
  • Tumor Protein p73
  • long non-coding RNA KIAA0495, human
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase
  • Temozolomide