Temozolomide-induced RNA interactome uncovers novel lncRNA regulatory loops in glioblastoma
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 (lncR...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
10 September 2020
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| In: |
Cancers
Year: 2020, Volume: 12, Issue: 9 |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12092583 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/cancers12092583 Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/2072-6694/12/9/2583 
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| Author Notes: | Sabrina Fritah, Arnaud Muller, Wei Jiang, Ramkrishna Mitra, Mohamad Sarmini, Monika Dieterle, Anna Golebiewska, Tao Ye, Eric Van Dyck, Christel Herold-Mende, Zhongming Zhao, Francisco Azuaje and Simone P. Niclou |
| Summary: | 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. |
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| Item Description: | Gesehen am 07.12.2020 |
| Physical Description: | Online Resource |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers12092583 |