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Significance Different mutations of the von Hippel–Lindau (VHL) tumor suppressor gene cause different subtypes of VHL hereditary cancer syndrome. Dysregulation of VHL’s canonical substrate, HIFα, cannot fully explain the complex genotype/phenotype manifestation within VHL disease. We describe an oxygen-sensitive function of VHL that regulates hydroxylated BIM-EL protein stability. Type 2C VHL mutants, which cause pheochromocytoma and paraganglioma (PCC/PGL) despite repressing HIFα, destabilize BIM-EL. Other genetic mutations linked to PCC/PGL, similar to loss of BIM-EL, protect from apoptosis upon nerve growth factor withdrawal. Dysregulation of BIM-EL might therefore contribute to the pathogenesis of VHL-related PCC/PGL. Loss of BIM-EL expression can lead to chemotherapy resistance in other VHL-related neoplasms and renders clear cell renal cell carcinoma cells insensitive to cisplatin.

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance