[en] 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.
Disciplines :
Oncology
Author, co-author :
FRITAH, Sabrina ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg.
Muller, Arnaud; Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg.
Jiang, Wei; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
Mitra, Ramkrishna; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37203, USA.
Sarmini, Mohamad; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg. ; Faculty of Science, Technology and Medicine, University of Luxembourg, L-4365 Esch-sur-Alzette, Luxembourg.
Dieterle, Monika; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg.
GOLEBIEWSKA, Anna ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg.
Ye, Tao ; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique, UMR7104, Institut National de la Santé et de la Recherche Médicale, U964, Université de Strasbourg, 67404 Illkirch, France.
Van Dyck, Eric; DNA Repair and Chemoresistance, Department of Oncology, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg.
Herold-Mende, Christel; Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, 69120 Heidelberg, Germany.
Zhao, Zhongming ; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37203, USA. ; School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
AZUAJE, Francisco ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg. ; Quantitative Biology Unit, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg.
NICLOU, Simone P. ; NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg L-1526, Luxembourg. ; Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway.
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