FAT1 is a novel upstream regulator of HIF1 and invasion of high grade glioma

The hypoxic microenvironment is an important contributor of glioblastoma (GBM) aggressiveness via HIF1, while tumour inflammation is profoundly influenced by FAT Atypical Cadherin (FAT1). This study was designed to explore the functional interaction and significance of FAT1 and HIF1 under severe hypoxia-mimicking tumour microenvironment in primary human tumours. We first identified a positive correlation of FAT1 with HIF1 and its target genes in GBM tumour specimens, revealing the significance of the FAT1-HIF1 axis in glioma cells. We found that severe hypoxia leads to an increased expression of FAT1 and HIF1 in U87MG and U373MG cells. To reveal the relevance of FAT1 under hypoxic conditions, we depleted endogenous FAT1 under hypoxia and found a substantial reduction in the expression of HIF1 and its downstream target genes like CA9, GLUT1, VEGFA, MCT4, HK2, BNIP3 and REDD1, as well as a significant reduction in the invasiveness in GBM cells. At the molecular level, under hypoxia the FAT1 depletion-associated reduction in HIF1 was due to compromised EGFR-Akt signaling as well as increased VHL-dependent proteasomal degradation of HIF1. In brief, for the first time, these results reveal an upstream master regulatory role of FAT1 in the expression and role of HIF1 under hypoxic conditions and that FAT1-HIF1 axis controls the invasiveness of GBM. Hence, FAT1 represents a novel potential therapeutic target for GBM. What's new? The hypoxic microenvironment is an important contributor of glioblastoma aggressiveness via HIF1 while tumor inflammation is profoundly influenced by FAT Atypical Cadherin (FAT1). This study explores the functional interaction of FAT1 and HIF1 in severe hypoxia-mimicking tumor microenvironments. The results show that FAT1 upregulation is critical for enhancing and maintaining high HIFI levels in tumors with severe hypoxia. FAT1 both increases HIFI transcription and decreases HIFI degradation in glioblastoma multiforme cell lines under hypoxic conditions. With FAT1 regulating the activity of HIF1 under hypoxic condition and the FAT1-HIF1 axis controlling the invasiveness of glioblastoma, FAT1 represents a novel potential therapeutic target for glioblastomas.