The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells

Abstract 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...

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Autores principales:	Solange Rivas, Patricio Silva, Montserrat Reyes, Hugo Sepúlveda, Luis Solano, Juan Acuña, Marisol Guerrero, Manuel Varas-Godoy, Andrew F. G. Quest, Martín Montecino, Vicente A. Torres
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70
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spelling	oai:doaj.org-article:162d2f8285b346ffa6b8d60dcfde1d702021-12-02T13:58:25ZThe RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells10.1038/s41598-020-79270-62045-2322https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d702020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79270-6https://doaj.org/toc/2045-2322Abstract 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-1α-dependent transcription, as shown by RNAi, pharmacological inhibition, chromatin immunoprecipitation and bioinformatics analyses, which identified a functional HIF-1α-binding site in the proximal promoter region of ALS2. Moreover, ALS2 and Rab5 activity were elevated both in a model of endogenous HIF-1α stabilization (renal cell carcinoma) and by following expression of stable non-hydroxylatable HIF-1α. 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-1α correlates with increased ALS2 expression. Hence, this study identifies ALS2 as a novel hypoxia-inducible gene associated with tumor progression and metastasis.Solange RivasPatricio SilvaMontserrat ReyesHugo SepúlvedaLuis SolanoJuan AcuñaMarisol GuerreroManuel Varas-GodoyAndrew F. G. QuestMartín MontecinoVicente A. TorresNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Solange Rivas Patricio Silva Montserrat Reyes Hugo Sepúlveda Luis Solano Juan Acuña Marisol Guerrero Manuel Varas-Godoy Andrew F. G. Quest Martín Montecino Vicente A. Torres The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
description	Abstract 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-1α-dependent transcription, as shown by RNAi, pharmacological inhibition, chromatin immunoprecipitation and bioinformatics analyses, which identified a functional HIF-1α-binding site in the proximal promoter region of ALS2. Moreover, ALS2 and Rab5 activity were elevated both in a model of endogenous HIF-1α stabilization (renal cell carcinoma) and by following expression of stable non-hydroxylatable HIF-1α. 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-1α correlates with increased ALS2 expression. Hence, this study identifies ALS2 as a novel hypoxia-inducible gene associated with tumor progression and metastasis.
format	article
author	Solange Rivas Patricio Silva Montserrat Reyes Hugo Sepúlveda Luis Solano Juan Acuña Marisol Guerrero Manuel Varas-Godoy Andrew F. G. Quest Martín Montecino Vicente A. Torres
author_facet	Solange Rivas Patricio Silva Montserrat Reyes Hugo Sepúlveda Luis Solano Juan Acuña Marisol Guerrero Manuel Varas-Godoy Andrew F. G. Quest Martín Montecino Vicente A. Torres
author_sort	Solange Rivas
title	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
title_short	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
title_full	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
title_fullStr	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
title_full_unstemmed	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
title_sort	rabgef als2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70
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The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells

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