Homo sapiens Raw sequence reads. Homo sapiens

Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor HIF-1α in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein GBE1, which has been causally implicated in tumor formation and metastasis in experimental models. Here we link these two elements by showing that hypoxia induces GBE1 expression through a functional hypoxia responsive element (HRE) in the GBE1 promoter. HIF-1α overexpression induced GBE1 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the GBE1 promoter. shRNA mediated-attenuation of HIF-1α or GBE1 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. GBE1 overexpression in HIF-1α-depleted cancer cells rescued this decrease while HIF-1α overexpression in GBE1- depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and GBE1 levels and an association of their co-expression to decreased patient survival.