Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression

Abstract Hypoxia-inducible factors (HIFs) play a central role in the transcriptional response to changes in oxygen availability. Stability of HIFs is regulated by multi-step reactions including recognition by the von Hippel-Lindau tumour suppressor protein (pVHL) in association with an E3 ligase com...

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Autores principales:	Wendi Sun, Hiroyuki Kato, Shojiro Kitajima, Kian Leong Lee, Katarina Gradin, Takashi Okamoto, Lorenz Poellinger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/54e312178c074791ab1118dadbc35278
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spelling	oai:doaj.org-article:54e312178c074791ab1118dadbc352782021-12-02T12:32:51ZInteraction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression10.1038/s41598-017-05685-32045-2322https://doaj.org/article/54e312178c074791ab1118dadbc352782017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05685-3https://doaj.org/toc/2045-2322Abstract Hypoxia-inducible factors (HIFs) play a central role in the transcriptional response to changes in oxygen availability. Stability of HIFs is regulated by multi-step reactions including recognition by the von Hippel-Lindau tumour suppressor protein (pVHL) in association with an E3 ligase complex. Here we show that pVHL physically interacts with fatty acid synthase (FASN), displacing the E3 ubiquitin ligase complex. This results in HIF-α protein stabilization and activation of HIF target genes even in normoxia such as during adipocyte differentiation. 25-hydroxycholesterol (25-OH), an inhibitor of FASN expression, also inhibited HIF target gene expression in cultured cells and in mouse liver. Clinically, FASN is frequently upregulated in a broad variety of cancers and has been reported to have an oncogenic function. We found that upregulation of FASN correlated with induction of many HIF target genes, notably in a malignant subtype of prostate tumours. Therefore, pVHL-FASN interaction plays a regulatory role for HIFs and their target gene expression.Wendi SunHiroyuki KatoShojiro KitajimaKian Leong LeeKatarina GradinTakashi OkamotoLorenz PoellingerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Wendi Sun Hiroyuki Kato Shojiro Kitajima Kian Leong Lee Katarina Gradin Takashi Okamoto Lorenz Poellinger Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression
description	Abstract Hypoxia-inducible factors (HIFs) play a central role in the transcriptional response to changes in oxygen availability. Stability of HIFs is regulated by multi-step reactions including recognition by the von Hippel-Lindau tumour suppressor protein (pVHL) in association with an E3 ligase complex. Here we show that pVHL physically interacts with fatty acid synthase (FASN), displacing the E3 ubiquitin ligase complex. This results in HIF-α protein stabilization and activation of HIF target genes even in normoxia such as during adipocyte differentiation. 25-hydroxycholesterol (25-OH), an inhibitor of FASN expression, also inhibited HIF target gene expression in cultured cells and in mouse liver. Clinically, FASN is frequently upregulated in a broad variety of cancers and has been reported to have an oncogenic function. We found that upregulation of FASN correlated with induction of many HIF target genes, notably in a malignant subtype of prostate tumours. Therefore, pVHL-FASN interaction plays a regulatory role for HIFs and their target gene expression.
format	article
author	Wendi Sun Hiroyuki Kato Shojiro Kitajima Kian Leong Lee Katarina Gradin Takashi Okamoto Lorenz Poellinger
author_facet	Wendi Sun Hiroyuki Kato Shojiro Kitajima Kian Leong Lee Katarina Gradin Takashi Okamoto Lorenz Poellinger
author_sort	Wendi Sun
title	Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression
title_short	Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression
title_full	Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression
title_fullStr	Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression
title_full_unstemmed	Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression
title_sort	interaction between von hippel-lindau protein and fatty acid synthase modulates hypoxia target gene expression
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/54e312178c074791ab1118dadbc35278
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Interaction between von Hippel-Lindau Protein and Fatty Acid Synthase Modulates Hypoxia Target Gene Expression

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