Lack of the ER stress response mediator ERO1 impairs cancer aggressiveness

De novo angiogenesis is a hallmark of aggressive tumors. Angiogenesis is the process of formation of new blood vessels that leads to the transformation of a dormant cluster of cells to a tumorigenic mass with metastatic potential. This process is regulated by the balance of antiangiogenic factors with the angiogenic ones, of which vascular endothelial growth factor (VEGFA) is the master regulator. Angiogenesis in cancer is triggered by hypoxia by activating hypoxia-inducible factor-1 (HIF-1), a transcription factor of angiogenic molecules, but is also regulated by Unfolded Protein Response (UPR), a homeostatic response to the stress of the endoplasmic reticulum (ER stress). Here, we have studied Endoplasmic reticulum oxidoreductin 1 (ERO1), an enzyme involved in disulfide bond formation, whose expression is regulated by hypoxia and ER stress, in the context of cancer angiogenesis. Lack of ERO1 in cancer cells under hypoxic conditions blunted the secretion of angiogenic factors and impairs the disulfide-bonded receptor-competent dimer of VEGFA. The analysis of VEGF glycosylation by endoglycosidase cleavage and mass spectrometry shows additional glycosylation of VEGF secreted by ERO1-devoid cells suggesting ERO1-dependent crosstalk between disulfide bond formation and glycosylation in VEGF. In conclusion, ERO1 participates in the folding of an active, receptor-competent VEGF and thus its inhibition can be harnessed as antiangiogenic therapy in cancers with pathological angiogenesis.