RSUME inhibits VHL and regulates its tumor suppressor function

GEREZ, J.; TEDESCO, L.; FUERTES, M.; BONFIGLIO, J.; BARTONTINI, M.; SILBERSTEIN, S.; WU, Y.; RENNER, U.; PAEZ PEREDA, M.; HOLSBOER, F.; STALLA, G.K.; ARZT, E.

ONCOGENE

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2015 vol. 34 p. 4855 - 4866

0950-9232

Somatic mutations or loss of von Hippel?Lindau (pVHL) happen in the majority of VHL disease tumors, which present aconstitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHLmodulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determinethe molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role ofRSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL andnegatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF-1 and 2α ubiquitinationand degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytomaand hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen-dependent degradation stability reporterassay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHLinteraction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in whichRSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2α,vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumorprogression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function