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.
Highlights
Hypoxia-inducible factors (HIFs) play a central role in the transcriptional response to changes in oxygen availability
We found that upregulation of fatty acid synthase (FASN) correlated with induction of many HIF target genes, notably in a malignant subtype of prostate tumours
FASN physically associates with pVHL. pVHL has multiple HIF-dependent and independent functions occurring through interactions with diverse cellular proteins
Summary
Wendi Sun[1], Hiroyuki Kato[1,2], Shojiro Kitajima[1], Kian Leong Lee 1, Katarina Gradin[3], Takashi Okamoto2 & Lorenz Poellinger[1,3]. 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. HIF-1α and HIF-2α regulate genes involved in a wide range of physiological events (e.g. angiogenesis, metabolisms, cell proliferation, apoptosis, etc.) with distinct spectrum[17,18] These regulations primarily cope with decreased oxygen consumption and the resulting deprivation of ATP as well as need for glucose uptake[19,20]. Downregulation of FASN efficiently decreased HIF-α protein levels in a manner dependent on pVHL in cultured cells and mice, whereas upregulation of FASN during adipocyte differentiation accompanied by an increase in HIF-α target gene expression. Together with data analysis of gene expression profiles of cancer patient samples, these findings strengthen the notion that HIF functionally interacts with metabolic pathways
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