LAUSR

Significance SMARCB1 is a tumor suppressor that is universally inactivated in renal medullary carcinoma (RMC), a highly aggressive malignancy that predominantly afflicts young individuals of African descent with sickle cell trait (SCT). We demonstrated using orthogonal in vitro and in vivo models that hypoxia induced by SCT leads to SMARCB1 degradation to protect cells from hypoxic stress. Accordingly, SMARCB1-deficient cells had a survival advantage in extreme hypoxic conditions. Furthermore, consistent with established clinical observations, SMARCB1 loss protected tumor cells from the hypoxia-inducing therapeutic inhibition of angiogenesis used for the treatment of other renal cell carcinomas. These results establish a physiological role for SMARCB1 in response to hypoxic stress and elucidate the connection between SCT and SMARCB1 loss observed in RMC.