title: Nuclear β-arrestin1 is a critical cofactor of hypoxia-inducible factor-1α signaling in endothelin-1-induced ovarian tumor progression.
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-1 receptor antagonist macitentan. Interestingly, ET(A)R/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/ET(A)R 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.
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cianfrocca
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Tocci
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosanò
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Caprara
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Sestito
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Valeriana
authors.initials: V
authors.lastname: Di Castro
authors.affiliation: Translational Research Functional Departmental Area, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bagnato
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018450:Disease Progression; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D000071559:beta-Arrestin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071559:beta-Arrestin 1
keywords: endothelin A receptor; endothelin-1; hypoxia-inducible factor-1α; ovarian carcinoma; β-arrestin1