The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
Author
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Rivas, Solange
Author
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Silva, Patricio
Author
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Reyes Rojas, Montserrat
Author
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Sepúlveda, Hugo
Author
dc.contributor.author
Solano, Luis
Author
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Acuña, Juan
Author
dc.contributor.author
Guerrero, Marisol
Author
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Varas Godoy, Manuel
Author
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Quest, Andrew F. G.
Author
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Montecino, Martín
Author
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Torres Gómez, Vicente
Admission date
dc.date.accessioned
2021-07-05T21:03:39Z
Available date
dc.date.available
2021-07-05T21:03:39Z
Publication date
dc.date.issued
2020
Cita de ítem
dc.identifier.citation
Scientific Reports (2020) 10:22302
es_ES
Identifier
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10.1038/s41598-020-79270-6
Identifier
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https://repositorio.uchile.cl/handle/2250/180416
Abstract
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Tumor hypoxia and the hypoxia inducible factor-1, HIF-1, play critical roles in cancer progression and metastasis. We previously showed that hypoxia activates the endosomal GTPase Rab5, leading to tumor cell migration and invasion, and that these events do not involve changes in Rab protein expression, suggesting the participation of intermediate activators. Here, we identified ALS2, a guanine nucleotide exchange factor that is upregulated in cancer, as responsible for increased Rab5-GTP loading, cell migration and metastasis in hypoxia. Specifically, hypoxia augmented ALS2 mRNA and protein levels, and these events involved HIF-1 alpha -dependent transcription, as shown by RNAi, pharmacological inhibition, chromatin immunoprecipitation and bioinformatics analyses, which identified a functional HIF-1 alpha -binding site in the proximal promoter region of ALS2. Moreover, ALS2 and Rab5 activity were elevated both in a model of endogenous HIF-1 alpha stabilization (renal cell carcinoma) and by following expression of stable non-hydroxylatable HIF-1 alpha. Strikingly, ALS2 upregulation in hypoxia was required for Rab5 activation, tumor cell migration and invasion, as well as experimental metastasis in C57BL/6 mice. Finally, immunohistochemical analyses in patient biopsies with renal cell carcinoma showed that elevated HIF-1 alpha correlates with increased ALS2 expression. Hence, this study identifies ALS2 as a novel hypoxia-inducible gene associated with tumor progression and metastasis.
es_ES
Patrocinador
dc.description.sponsorship
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT
1180495
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDAP
15130011
15090007
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT
3170660
1170925
1170878
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)