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

ABSTRACT: Hypoxia-inducible factor-1? (HIF-1?) 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-1? 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 ?-arrestin1 (?-arr1) to HIF-1? signalling. In epithelial ovarian cancer (EOC) cells, ET-1/ET(A)R axis induced vascular-endothelial growth factor (VEGF) expression through HIF-1? nuclear accumulation. In these cells, activation of ET(A)R by ET-1, by mimicking hypoxia, promoted the nuclear interaction between ?-arr1 and HIF-1? and the recruitment of p300 acetyltransferase to hypoxia response elements on the target gene promoters, resulting in enhanced histone acetylation, and HIF-1? target gene transcription. Indeed, ?-arr1-HIF-1? 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 ?-arr1 or HIF-1? silencing or by pharmacological treatment with the dual ET-1 receptor antagonist macitentan. Interestingly, ET(A)R/?-arr1 promoted the self-amplifying HIF-1?-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 ?-arr1, inhibits intravasation and metastasis formation. Collectively, these findings reveal the interplay of ?-arr1 with HIF-1? 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 ?-arr1/HIF-1? pathway by using macitentan may impair EOC progression.

SUBMITTER: Cianfrocca R 

PROVIDER: S-EPMC4951250 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature