Nuclear β-arrestin1 is a critical cofactor of hypoxia-inducible factor-1α signaling in endothelin-1-induced ovarian tumor progression

Oncotarget
Roberta CianfroccaAnna Bagnato

Abstract

Hypoxia-inducible factor-1α (HIF-1α) mediates the response to hypoxia or other stimuli, such as growth factors, including endothelin-1 (ET-1), to promote malignant progression in numerous tumors. The importance of cofactors that regulate HIF-1α signalling within tumor is not well understood. Here we elucidate that ET-1/ET(A) receptor (ET(A)R)-induced pathway physically and functionally couples the scaffold protein β-arrestin1 (β-arr1) to HIF-1α signalling. In epithelial ovarian cancer (EOC) cells, ET-1/ET(A)R axis induced vascular-endothelial growth factor (VEGF) expression through HIF-1α nuclear accumulation. In these cells, activation of ET(A)R by ET-1, by mimicking hypoxia, promoted the nuclear interaction between β-arr1 and HIF-1α and the recruitment of p300 acetyltransferase to hypoxia response elements on the target gene promoters, resulting in enhanced histone acetylation, and HIF-1α target gene transcription. Indeed, β-arr1-HIF-1α interaction regulated the enhanced expression and release of downstream targets, such as ET-1 and VEGF, required for tumor cell invasion and pro-angiogenic effects in endothelial cells. These effects were abrogated by β-arr1 or HIF-1α silencing or by pharmacological treatment with the dual ET-...Continue Reading

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Citations

Jul 31, 2016·Journal of Experimental & Clinical Cancer Research : CR·Laura Rosanò, Anna Bagnato
Feb 14, 2018·Proceedings of the National Academy of Sciences of the United States of America·Francesca Di ModugnoLaura Rosanò
Mar 10, 2017·The Journal of Maternal-fetal & Neonatal Medicine : the Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians·Hacer UyanikogluAdnan Incebiyik
Feb 28, 2018·Journal of Ovarian Research·Ke ZhangBaoyun Zhang
Aug 2, 2017·Expert Opinion on Therapeutic Targets·Laura RosanòAnna Bagnato
Jan 26, 2021·Frontiers in Oncology·Anna RussignanCristina Tecchio
Jan 11, 2021·Journal of Experimental & Clinical Cancer Research : CR·Piera TocciAnna Bagnato
Aug 13, 2021·Frontiers in Cell and Developmental Biology·Yuyu YangYong Xu
Apr 8, 2020·ACS Pharmacology & Translational Science·Abanoub A Gad, Nariman Balenga

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Methods Mentioned

BETA
ubiquitination
nuclear translocation
histone acetylation
ELISA
co-IP
immunoprecipitation
ChIP
acetylation
PCR
xenografts

Software Mentioned

ImageJ
SPSS

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