Implication of LncRNAs in chemoresistance in Glioblastom

Project Details


Glioblastoma (GBM) is an aggressive, incurable cancer and resistance to chemotherapy is a major cause of treatment failure. The Norlux Neuro-Oncology laboratory focuses on the development of novel therapeutic approaches against this deadly disease and has established a large number of clinically relevant animal and cellular models of GBM. Using whole genome RNA sequencing on models of different aggressiveness, we identified novel RNA targets involved in the chemoresistance to Temozolomide (TMZ). In particular, we identified that TMZ strongly affects the expression of a novel family of regulatory RNAs, the long non-coding RNAs (LncRNAs). Next, by comparing our transcriptomic results with publicly available datasets of LncRNA expression in GBM patients, we identified four LncRNAs regulated by TMZ, which, in addition are prognostic markers of patient’s survival.
This project will focus on the functional investigation of two of these LncRNAs: UBR5-AS1 and GAS6-AS1. Indeed, our systems analysis approach revealed that these two LncRNAs share common regulators in a transcriptional network. In addition, UBR5-AS1 and GAS6-AS1 are predicted to be transcribed, respectively, in the opposite strand of aubiquitin enzyme that has a function in DNA damage, UBR5, and GAS6, the ligand of a kinase deregulated in cancer.
As the function of these LncRNAs is unknown, we will first characterize them at the molecular level and determine their subcellular localization to guide subsequent functional studies. For this purpose, we will investigate signaling pathways involving UBR5-AS1 and GAS6-AS1 using large scale experiments, such as RNA immunoprecipitation followed by mass spectrometry to identify protein binding partners, as well as the analysis of chromatin structure changes induced by TMZ, in the presence and absence of UBR5-AS1 and GAS6-AS1.
Finally, we will impact on UBR5-AS1 and GAS6-AS1 activity using aptamers and characterize GBM development and chemosensitivity in vitro and in vivo, using orthotopic GBM xenotransplants. In conclusion, this project will provide new knowledge on the function of two clinically relevant LncRNAs, in GBM biology, as well as their potential use as chemosensitizers.
Effective start/end date1/04/1731/03/21


  • FNRS - Fonds National de la Recherche Scientifique: €112,846.00


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