Leukemia associated RUNX1T1 gene reduced proliferation and invasiveness of glioblastoma cells

RUNX1T1 has been found to be mutated in different cancers such as prostate, lung, colon, and breast cancer. A recent computational study involving the TCGA database of glioma patients found RUNX1T1 as one of the down-regulated driver genes associated with poor overall survival of glioma patients. Hypoxia-inducible factor 1 alpha (HIF1 alpha) is upregulated in glioma and has been associated with the severity and drug resistance of glioma. Previously, we have shown that RUNX1T3 degrades HIF1 alpha affecting the proliferation of leukemia cells. We hypothesize that RUNXIT1 might be associated with the growth and development of glioma through the regulation of HIF1 alpha. We have evaluated the expression level of RUNX1T1 at different stages of glioma and the effect of RUNX1T1 on the proliferation and invasiveness of glioblastoma cells in vitro. We further looked at the effect of RUNX1T1 on the expression and stability of HIF1 alpha in vitro. Expression of RUNX1T1 was significantly downregulated, both at RNA and protein levels in glioma samples as studied by quantitative real-time polymerase chain reaction and immunohistochemistry. While expression of HIF1 alpha was higher in glioma tissues compared with its level in the normal brain. In vitro studies demonstrated that RUNXIT1 interacted with HIF1 alpha and recruited HIF1 alpha modification factor such as PHD2 and GSK3 beta causing hydroxylation of HIF1 alpha following ubiquitination by FBW7. RUNX1T1 led to the degradation of HIF1 alpha and decreased proliferation/invasiveness of glioblastoma cell lines. Further, RUNX1T1 increased the effectiveness of temozolomide (TMZ), a conventional glioma drug toward glioblastoma cell lines. This study indicates that downregulation of RUNX1T1 might play an important role in the severity and development of glioma.