Transcriptional Control of Brain Tumour Stem Cell Fate by a Carbohydrate Binding Protein [article]

Ahmad Sharanek, Audrey Burban, Aldo Hernandez-Corchado, Idris Fatakdawala, Ariel Madrigal, Hamed S Najafabadi, Vahab D Soleimani, Arezu Jahani-Asl
2021 bioRxiv   pre-print
Brain tumour stem cells (BTSC) and intratumoural heterogeneity represent major challenges for the effective treatment of glioblastoma. EGFRvIII is a key oncogenic protein in glioblastoma, however, the mechanisms that regulate BTSC fate in EGFRvIII subtype of tumours remain poorly characterized. Here, we report our discovery of the lectin, galactoside-binding, soluble 1 (LGALS1) gene, encoding the carbohydrate binding protein, galectin1, as a key regulator of BTSC fate in glioblastoma tumours
more » ... bouring the EGFRvIII mutation. Genetic deletion of LGALS1 alters gene expression profile of BTSCs, leads to cell cycle defects and impairs self-renewal. Using a combination of pharmacological and genetic approaches in preclinical animal models, we establish that inhibition of LGALS1 signalling in BTSCs suppresses tumourigenesis, prolongs lifespan, and improves glioblastoma response to radiation-therapy. Mechanistically, two key transcription factors are involved in the regulation of LGALS1 expression and function. Upstream, STAT3 directly binds to the promoter of LGALS1 and robustly upregulates its expression. Downstream, galectin1 forms a complex with the transcription factor homeobox5 (HOXA5) to reprogram BTSC transcriptional landscape and drive glioblastoma tumourigenesis. Our data unravel a novel LGALS1/HOXA5 oncogenic signalling pathway that is required for BTSC maintenance and the pathogenesis of EGFRvIII subtype of glioblastoma.
doi:10.1101/2021.04.14.439704 fatcat:st6ju2htxzacxj5ahw653gdhqy