Mutant versions of von Hippel-Lindau (VHL) can protect HIF1α from SART1-mediated degradation in clear-cell renal cell carcinoma.
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor drives the development of clear-cell renal cell carcinoma (ccRCC) through hypoxia-inducible factors (HIFs). Although ccRCC cells exhibit constitutive normoxic HIF signaling, the potential role of hypoxia in this setting is not fully understood. We show here that the ccRCC cell lines RCC4 and RCC10, which express mutant versions of VHL, have reduced HIF1α expression in hypoxia, whereas HIF2α expression is increased or not affected. Similar findings were observed in normoxia after abrogation of prolyl hydroxylase activity by siRNA or pharmacological inhibition, and by siRNA inhibition of mutant VHL. This reduction of HIF1α protein is due to proteasome-dependent degradation and is mediated by the E3 ubiquitin ligase SART1. HIF1α degradation favors ccRCC proliferation, in line with the previously recognized tumor suppressor capability of HIF1α. Our data indicate that mutant VHL can protect HIF1α from SART1-dependent degradation in normoxic conditions, but this protection is lost in hypoxic settings, favoring hypoxia-dependent ccRCC proliferation. This mechanism of HIF1α degradation might operate in some VHL-related clear-cell renal carcinomas in which the deletion of HIF1α locus does not occur.
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Á
Á
Ordóñez-Navadijo
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
E
E
Fuertes-Yebra
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
B
B
Acosta-Iborra
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
E
E
Balsa
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
A
A
Elorza
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
J
J
Aragonés
Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.|Universidad Central del Ecuador, Quito, Ecuador.
M O
MO
Landazuri
D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
D000951:Antigens, Neoplasm; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017411:Ribonucleoproteins, Small Nuclear; C431323:SART1 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human