Research Papers:

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

Roberta Cianfrocca, Piera Tocci, Laura Rosanò, Valentina Caprara, Rosanna Sestito, Valeriana Di Castro and Anna Bagnato _

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Oncotarget. 2016; 7:17790-17804. https://doi.org/10.18632/oncotarget.7461

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Roberta Cianfrocca1,*, Piera Tocci1,*, Laura Rosanò1, Valentina Caprara1, Rosanna Sestito1, Valeriana Di Castro1 and Anna Bagnato1

1 Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy

* These authors have contributed equally to this work

Correspondence to:

Anna Bagnato, email:

Keywords: ovarian carcinoma, endothelin-1, β-arrestin1, hypoxia-inducible factor-1α, endothelin A receptor

Received: December 10, 2015 Accepted: February 07, 2016 Published: February 17, 2016


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/ETA receptor (ETAR)-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/ETAR axis induced vascular-endothelial growth factor (VEGF) expression through HIF-1α nuclear accumulation. In these cells, activation of ETAR 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-1 receptor antagonist macitentan. Interestingly, ETAR/β-arr1 promoted the self-amplifying HIF-1α-mediated transcription of ET-1 that sustained a regulatory circuit involved in invasive and angiogenic behaviors. In a murine orthotopic model of metastatic human EOC, treatment with macitentan, or silencing of β-arr1, inhibits intravasation and metastasis formation. Collectively, these findings reveal the interplay of β-arr1 with HIF-1α in the complexity of ET-1/ETAR signalling, mediating epigenetic modifications directly involved in the metastatic process, and suggest that targeting ET-1-dependent β-arr1/HIF-1α pathway by using macitentan may impair EOC progression.

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