Hypoxia-Associated Factor (HAF) Mediates Neurofibromin Ubiquitination and Degradation Leading to Ras-ERK Pathway Activation in Hypoxia.
Mol Cancer Res
; 17(5): 1220-1232, 2019 05.
Article
em En
| MEDLINE
| ID: mdl-30705246
ABSTRACT
Low oxygen or hypoxia is a feature of all solid tumors and has been associated with aggressive disease. Here, we describe a novel mechanism for the hypoxia-dependent degradation of the Ras-GTPase-activating protein neurofibromin, by hypoxia-associated factor (HAF). We have previously characterized HAF as an oxygen-independent ubiquitin ligase for HIF-1α. Here, we show that HAF promotes neurofibromin ubiquitination and degradation independently of oxygen and pVHL, resulting in Ras-ERK pathway activation. Hypoxia enhanced HAFneurofibromin binding independently of HAF-SUMOylation, whereas HAF knockdown increased neurofibromin levels primarily in hypoxia, supporting the role of HAF as a hypoxia-specific neurofibromin regulator. HAF overexpression increased p-ERK levels and promoted resistance of clear cell kidney cancer (ccRCC) cells to sorafenib and sunitinib in both normoxia and hypoxia. However, a greater-fold increase in sorafenib/sunitinib resistance was observed during hypoxia, particularly in pVHL-deficient cells. Intriguingly, HAF-mediated resistance was HIF-2α-dependent in normoxia, but HIF-2α-independent in hypoxia indicating two potential mechanisms of HAF-mediated resistance a HIF-2α-dependent pathway dominant in normoxia, and the direct activation of the Ras-ERK pathway through neurofibromin degradation dominant in hypoxia. Patients with ccRCC with high HAF transcript or protein levels showed significantly decreased overall survival compared with those with low HAF. Thus, we establish a novel, nonmutational pathway of neurofibromin inactivation through hypoxia-induced HAF-mediated degradation, leading to Ras-ERK activation and poor prognosis in ccRCC. IMPLICATIONS We describe a novel mechanism of neurofibromin degradation induced by hypoxia that leads to activation of the prooncogenic Ras-ERK pathway and resistance to therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma de Células Renais
/
Resistencia a Medicamentos Antineoplásicos
/
Neurofibromina 1
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Peptídeos e Proteínas de Sinalização Intracelular
/
Neoplasias Renais
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Mol Cancer Res
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Ano de publicação:
2019
Tipo de documento:
Article