Estrogen receptor beta inhibits transcriptional activity of hypoxia inducible factor-1 through the downregulation of arylhydrocarbon receptor nuclear translocator.

ABSTRACT: INTRODUCTION: Estrogen receptor (ER) ? is predicted to play an important role in prevention of breast cancer development and metastasis. We have shown previously that ER? inhibits hypoxia inducible factor (HIF)-1? mediated transcription, but the mechanism by which ER? works to exert this effect is not understood. METHODS: Vascular endothelial growth factor (VEGF) was measured in conditioned medium by enzyme-linked immunosorbent assays. Reverse transcription polymerase chain reaction (RT-PCR), Western blotting, immunoprecipitation, luciferase assays and chromatin immunoprecipitation (ChIP) assays were used to ascertain the implication of ER? on HIF-1 function. RESULTS: In this study, we found that the inhibition of HIF-1 activity by ER? expression was correlated with ER?'s ability to degrade aryl hydrocarbon receptor nuclear translocator (ARNT) via ubiquitination processes leading to the reduction of active HIF-1?/ARNT complexes. HIF-1 repression by ER? was rescued by overexpression of ARNT as examined by hypoxia-responsive element (HRE)-driven luciferase assays. We show further that ER? attenuated the hypoxic induction of VEGF mRNA by directly decreasing HIF-1? binding to the VEGF gene promoter. CONCLUSIONS: These results show that ER? suppresses HIF-1?-mediated transcription via ARNT down-regulation, which may account for the tumour suppressive function of ER?.

SUBMITTER: Lim W 

PROVIDER: S-EPMC3219195 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature