Treatment with Brusatol inhibits oncogenic transcription factors NRF2 and TAZ, reducing glioma stem cells survival

Resumen del trabajo presentado al 5th Symposium on Biomedical Research: "Advances and Perspectives In Pharmacology, Drug Toxicity and Pharmacogenetics", celebrado en Madrid del 15 al 16 de marzo de 2018.Glioblastomas are nervous system solid tumours with poor prognosis and hard treatment, since they present glioma stem cells (GSCs), a subpopulation of cells responsible for resistance to chemotherapy and radiotherapy, which lead to tumour recurrence. NRF2 and TAZ transcription factors are involved in tumour development, but their role in regulation of cancer stem cells (CSCs) and their possible crosstalk have not been explored. Our studies demonstrate a correlation between NRF2 and TAZ expression and the prognosis of patients with glioma. Knock-down of NRF2 in human glioblastoma explants and glioblastoma cell lines, decreased messenger RNA and protein levels of TAZ and its transcriptional signature. In addition, we identified functional NRF2- binding sites (Antioxidant Response Element, ARE) in the promoter region of the TAZ encoding gene (WWTR1). Besides, NRF2 knock-down reduces cell growth both in vitro and in vivo, being rescued with TAZ overexpression. Consequently, we conclude that at least part of the tumorigenic capacity of NRF2 is TAZ-dependent. Following this evidence, we have used NRF2 inhibitor Brusatol. This treatment reduced TAZ levels and GSCs growth in the same way as NRF2 knock-down. Because of this, we propose NRF2 and TAZ pharmacological inhibition as a novel glioblastoma therapy.Peer reviewe