title: EAF2 suppresses hypoxia-induced factor 1α transcriptional activity by disrupting its interaction with coactivator CBP/p300.
abstract: Previous studies revealed that the potential tumor suppressor EAF2 binds to and stabilizes pVHL, suggesting that EAF2 may function by disturbing the hypoxia signaling pathway. However, the extent to which EAF2 affects hypoxia and the mechanisms underlying this activity remain largely unknown. In this study, we found that EAF2 is a hypoxia response gene harboring the hypoxia response element (HRE) in its promoter. By taking advantage of the pVHL-null cell lines RCC4 and 786-O, we demonstrated that hypoxia-induced factor 1α (HIF-1α), but not HIF-2α, induced EAF2 under hypoxia. Subsequent experiments showed that EAF2 bound to and suppressed HIF-1α but not HIF-2α transactivity. In addition, we observed that EAF2 inhibition of HIF-1α activity resulted from the disruption of p300 recruitment and that this occurred independently of FIH-1 (factor inhibiting HIF-1) and Sirt1. Furthermore, we found that EAF2 protected cells against hypoxia-induced cell death and inhibited cellular uptake of glucose under hypoxic conditions, suggesting that EAF2 indeed may act by modulating the hypoxia-signaling pathway. Our findings not only uncover a unique feedback regulation loop between EAF2 and HIF-1α but also provide a novel insight into the mechanism of EAF2 tumor suppression.
authors.affiliation: Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, People's Republic of China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Mei
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
authors.forename: Wuhan
authors.initials: W
authors.lastname: Xiao
mesh_terms: D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C472771:EAF2 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D005947:Glucose