Acidosis Acts through HSP90 in a PHD/VHL-Independent Manner to Promote HIF Function and Stem Cell Maintenance in Glioma

Hypoxia is a common feature of solid tumors that affects their progression by maintaining cancer stem-like cells (CSC). Among the changes promoted by hypoxia is a metabolic shift resulting in acidification of the tumor microenvironment. Here we show that in glioma hypoxia and acidosis functionally cooperate in inducing HIF transcription factors and CSC maintenance. We found these effects did not involve the classical PHD/VHL pathway for HIF upregulation, but instead involved the stress-induced chaperone protein HSP90. Genetic or pharmacological inactivation of HSP90 inhibited HIF levels and abolished the self-renewal and tumorigenic properties of CSC induced by acidosis. In clinical specimens of glioma, HSP90 was upregulated in the hypoxic niche and was correlated with a CSC phenotype. Our findings highlight the role of tumor acidification within the hypoxic niche in the regulation of HIF and CSC function through HSP90, with implications for therapeutic strategies to target CSC in gliomas and other hypoxic tumors.