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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Autor*in:	Solange Rivas [verfasserIn] Patricio Silva [verfasserIn] Montserrat Reyes [verfasserIn] Hugo Sepúlveda [verfasserIn] Luis Solano [verfasserIn] Juan Acuña [verfasserIn] Marisol Guerrero [verfasserIn] Manuel Varas-Godoy [verfasserIn] Andrew F. G. Quest [verfasserIn] Martín Montecino [verfasserIn] Vicente A. Torres [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Übergeordnetes Werk:	In: Scientific Reports - Nature Portfolio, 2011, 10(2020), 1, Seite 14
Übergeordnetes Werk:	volume:10 ; year:2020 ; number:1 ; pages:14

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41598-020-79270-6

Katalog-ID:	DOAJ068552491

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allfields	10.1038/s41598-020-79270-6 doi (DE-627)DOAJ068552491 (DE-599)DOAJ162d2f8285b346ffa6b8d60dcfde1d70 DE-627 ger DE-627 rakwb eng Solange Rivas verfasserin aut The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Patricio Silva verfasserin aut Montserrat Reyes verfasserin aut Hugo Sepúlveda verfasserin aut Luis Solano verfasserin aut Juan Acuña verfasserin aut Marisol Guerrero verfasserin aut Manuel Varas-Godoy verfasserin aut Andrew F. G. Quest verfasserin aut Martín Montecino verfasserin aut Vicente A. Torres verfasserin aut In Scientific Reports Nature Portfolio, 2011 10(2020), 1, Seite 14 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:10 year:2020 number:1 pages:14 https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70 kostenfrei https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2020 1 14
spelling	10.1038/s41598-020-79270-6 doi (DE-627)DOAJ068552491 (DE-599)DOAJ162d2f8285b346ffa6b8d60dcfde1d70 DE-627 ger DE-627 rakwb eng Solange Rivas verfasserin aut The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Patricio Silva verfasserin aut Montserrat Reyes verfasserin aut Hugo Sepúlveda verfasserin aut Luis Solano verfasserin aut Juan Acuña verfasserin aut Marisol Guerrero verfasserin aut Manuel Varas-Godoy verfasserin aut Andrew F. G. Quest verfasserin aut Martín Montecino verfasserin aut Vicente A. Torres verfasserin aut In Scientific Reports Nature Portfolio, 2011 10(2020), 1, Seite 14 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:10 year:2020 number:1 pages:14 https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70 kostenfrei https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2020 1 14
allfields_unstemmed	10.1038/s41598-020-79270-6 doi (DE-627)DOAJ068552491 (DE-599)DOAJ162d2f8285b346ffa6b8d60dcfde1d70 DE-627 ger DE-627 rakwb eng Solange Rivas verfasserin aut The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Patricio Silva verfasserin aut Montserrat Reyes verfasserin aut Hugo Sepúlveda verfasserin aut Luis Solano verfasserin aut Juan Acuña verfasserin aut Marisol Guerrero verfasserin aut Manuel Varas-Godoy verfasserin aut Andrew F. G. Quest verfasserin aut Martín Montecino verfasserin aut Vicente A. Torres verfasserin aut In Scientific Reports Nature Portfolio, 2011 10(2020), 1, Seite 14 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:10 year:2020 number:1 pages:14 https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70 kostenfrei https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2020 1 14
allfieldsGer	10.1038/s41598-020-79270-6 doi (DE-627)DOAJ068552491 (DE-599)DOAJ162d2f8285b346ffa6b8d60dcfde1d70 DE-627 ger DE-627 rakwb eng Solange Rivas verfasserin aut The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Patricio Silva verfasserin aut Montserrat Reyes verfasserin aut Hugo Sepúlveda verfasserin aut Luis Solano verfasserin aut Juan Acuña verfasserin aut Marisol Guerrero verfasserin aut Manuel Varas-Godoy verfasserin aut Andrew F. G. Quest verfasserin aut Martín Montecino verfasserin aut Vicente A. Torres verfasserin aut In Scientific Reports Nature Portfolio, 2011 10(2020), 1, Seite 14 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:10 year:2020 number:1 pages:14 https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70 kostenfrei https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2020 1 14
allfieldsSound	10.1038/s41598-020-79270-6 doi (DE-627)DOAJ068552491 (DE-599)DOAJ162d2f8285b346ffa6b8d60dcfde1d70 DE-627 ger DE-627 rakwb eng Solange Rivas verfasserin aut The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Patricio Silva verfasserin aut Montserrat Reyes verfasserin aut Hugo Sepúlveda verfasserin aut Luis Solano verfasserin aut Juan Acuña verfasserin aut Marisol Guerrero verfasserin aut Manuel Varas-Godoy verfasserin aut Andrew F. G. Quest verfasserin aut Martín Montecino verfasserin aut Vicente A. Torres verfasserin aut In Scientific Reports Nature Portfolio, 2011 10(2020), 1, Seite 14 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:10 year:2020 number:1 pages:14 https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70 kostenfrei https://doi.org/10.1038/s41598-020-79270-6 kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2020 1 14
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authorswithroles_txt_mv	Solange Rivas @@aut@@ Patricio Silva @@aut@@ Montserrat Reyes @@aut@@ Hugo Sepúlveda @@aut@@ Luis Solano @@aut@@ Juan Acuña @@aut@@ Marisol Guerrero @@aut@@ Manuel Varas-Godoy @@aut@@ Andrew F. G. Quest @@aut@@ Martín Montecino @@aut@@ Vicente A. Torres @@aut@@
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author	Solange Rivas
spellingShingle	Solange Rivas misc Medicine misc R misc Science misc Q The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
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topic_title	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
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title	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
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title_full	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
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author_browse	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
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title_sort	rabgef als2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
title_auth	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	The RabGEF ALS2 is a hypoxia inducible target associated with the acquisition of aggressive traits in tumor cells
url	https://doi.org/10.1038/s41598-020-79270-6 https://doaj.org/article/162d2f8285b346ffa6b8d60dcfde1d70 https://doaj.org/toc/2045-2322
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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. 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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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