Temozolomide-induced RNA interactome uncovers novel lncRNA regulatory loops in glioblastoma.

  • NORLUX Neuro-Oncology Laboratory
  • Quantitative Biology Unit
  • DNA Repair and Chemoresistance
September 10, 2020 By:
  • Fritah S
  • Muller A
  • Jiang W
  • Mitra R
  • Sarmini M
  • Dieterle M
  • Golebiewska A
  • Ye T
  • Van Dyck E
  • Herold-Mende C
  • Zhao Z
  • Azuaje F
  • Niclou SP.

Resistance to chemotherapy by temozolomide (TMZ) is a major cause of glioblastoma (GBM) recurrence. So far, attempts to characterize factors that contribute to TMZ sensitivity have largely focused on protein-coding genes, and failed to provide effective therapeutic targets. Long noncoding RNAs (lncRNAs) are essential regulators of epigenetic-driven cell diversification, yet, their contribution to the transcriptional response to drugs is less understood. Here, we performed RNA-seq and small RNA-seq to provide a comprehensive map of transcriptome regulation upon TMZ in patient-derived GBM stem-like cells displaying different drug sensitivity. In a search for regulatory mechanisms, we integrated thousands of molecular associations stored in public databases to generate a background "RNA interactome". Our systems-level analysis uncovered a coordinated program of TMZ response reflected by regulatory circuits that involve transcription factors, mRNAs, miRNAs, and lncRNAs. We discovered 22 lncRNAs involved in regulatory loops and/or with functional relevance in drug response and prognostic value in gliomas. Thus, the investigation of TMZ-induced gene networks highlights novel RNA-based predictors of chemosensitivity in GBM. The computational modeling used to identify regulatory circuits underlying drug response and prioritizing gene candidates for functional validation is applicable to other datasets.

2020 Sep. Cancers.12(9).
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