FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma

Oct 11, 2017International journal of cancer

FAT1 influences genes related to cell change and stem-like traits in low-oxygen brain tumors

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Abstract

FAT1 expression was upregulated in ≥39% of glioblastoma tumors (n = 31) and positively correlated with multiple markers of epithelial-mesenchymal transition and stemness.

FAT1 is associated with increased expression of markers related to epithelial-mesenchymal transition and stemness in glioblastoma.
Significant positive correlations were observed between FAT1 and various markers, including LOX, Vimentin, SOX2, and HIF-1α.
In vitro studies showed that exposure to severe hypoxia elevated the expression of FAT1 and related markers compared to normoxic conditions.
Knockdown of FAT1 in glioblastoma cells resulted in reduced levels of epithelial-mesenchymal transition and stemness markers.
HIF-1α knockdown diminished the expression of most studied markers but had a lesser effect on Nestin and SOX2, indicating FAT1's distinct regulatory role.
Reduction in soft-agar colony formation in hypoxic conditions following FAT1 knockdown suggests its importance in glioblastoma cell growth.

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Glioblastoma (GBM) is characterized by the presence of hypoxia, stemness and local invasiveness. We have earlier demonstrated that FAT1 promotes invasiveness, inflammation and upregulates HIF-1α expression and its signaling in hypoxic GBM. Here, we have identified the role of FAT1 in regulating EMT (epithelial-mesenchymal transition) and stemness characteristics in GBM. The expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/VEGF/PGK1/CA9) was upregulated in ≥39% of GBM tumors (n = 31) with significant positive correlation (p ≤ 0.05) of the expression of FAT1 with LOX/Vimentin/SOX2/HIF-1α/PGK1/VEGF/CA9. Furthermore, positive correlation (p ≤ 0.01) of FAT1 with Vimentin/N-cad/SOX2/REST/HIF-1α has been observed in TCGA GBM-dataset (n = 430). Analysis of cells (U87MG/A172) exposed to severe hypoxia (0.2%O) revealed elevated mRNA expression of FAT1, EMT (Snail/LOX/Vimentin/N-cad), stemness (SOX2/OCT4/Nestin/REST) and hypoxia markers (HIF-1α/PGK1/VEGF/CA9) as compared to their normoxic (20%O) counterparts. FAT1 knockdown in U87MG/A172 maintained in severe hypoxia and in normoxic primary glioma cultures led to significant reduction of EMT/stemness markers as compared to controls. HIF-1α knockdown in U87MG cells markedly reduced the expression of all the EMT/stemness markers studied except for Nestin and SOX2 which were more under the influence of FAT1. This indicates FAT1 has a novel regulatory effect on EMT/stemness markers both via or independent of HIF-1α. The functional relevance of our study was corroborated by significant reduction in the number of soft-agar colonies formed in hypoxic-siFAT1 treated U87MG cells. Hence, our study for the first time reveals FAT1 as a novel regulator of EMT/stemness in hypoxic GBM and suggests FAT1 as a potential therapeutic candidate. 2 2

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FAT1 modulates EMT and stemness genes expression in hypoxic glioblastoma

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