β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling

Abstract

Despite the fundamental pathophysiological importance of b-catenin in tumor progression, the mechanism underlying its final transcriptional output has been partially elucidated. Here, we report that b-arrestin-1 (b-arr1) is an epigenetic regulator of endothelin (ET)-1-induced b-catenin signaling in epithelial ovarian cancer (EOC). In response to ET A receptor (ET A R) activation by ET-1, b-arr1 increases its nuclear translocation and direct binding to b-catenin. This in turn enhanced b-catenin nuclear accumulation and transcriptional activity, which was prevented by expressing a mutant b-arr1 incapable of nuclear distribution. b-arr1-b-catenin interaction controls b-catenin target gene expressions, such as ET-1, Axin 2, Matrix metalloproteinase 2, and Cyclin D1, by promoting histone deacetylase 1 (HDAC1) dissociation and the recruitment of p300 acetyltransferase on these promoter genes, resulting in enhanced H3 and H4 histone acetylation, and gene transcription, required for cell migration, invasion and epithelial-to-mesenchymal transition. These effects are abrogated by b-arr1 silencing or by mutant b-arr1, as well as by b-catenin or p300 silencing, confirming that nuclear b-arr1 forms a functional complex capable of regulating epigenetic changes in b-catenindriven invasive behavior. In a murine orthotopic model of metastatic human EOC, silencing of b-arr1 or mutant b-arr1 expression, as well as ET A R blockade, inhibits metastasis. In human EOC tissues, b-arr1-b-catenin nuclear complexes are selectively enriched at b-catenin target gene promoters, correlating with tumor grade, confirming a direct in vivo b-arr1-b-catenin association at specific set of genes involved in EOC progression. Collectively, our study provides insights into how a b-arr1-mediated epigenetic mechanism controls b-catenin activity, unraveling new components required for its nuclear function in promoting metastasis.Oncogene ( 1,2 b-arrs, consisting of b-arr1 and b-arr2, are involved in G-protein-coupled receptor signaling, and guide the receptor signals also in malignant cells. [3][4][5][6][7][8][9][10][11][12] A global proteomics analysis of b-arr1-interacting proteins demonstrated that b-arr1 interactions take place not only in the cytoplasm, but also in the nucleus, 13 suggesting that b-arr1 has a role in transcriptional regulation in different human cells.14-16 Previous studies indicate that under d-or k-opioid receptor stimulations, nuclear b-arr1 specifically accumulates at p27 and c-fos promoters through scaffolding cyclic adenosine monophosphate responseelement (CRE) binding protein and histone acetyltransferase p300, thus enhancing local histone acetylation and gene transcription.

Endothelin A Receptor/β-Arrestin Signaling to the Wnt Pathway Renders Ovarian Cancer Cells Resistant to Chemotherapy

“…Chromatin was extracted from cells and chromatin immunoprecipitation (ChIP) assays were performed as previously described (18).…”

“…Aberrant accumulation of b-catenin correlates with EOC tumor grade and poor survival (20,21) and deregulation of Wnt/b-catenin signaling is a key factor in inducing and maintaining chemoresistance in EOC (22,23). Although recent evidence suggests that downstream of ET A R, b-arr1 serves as component of functional complexes for b-catenin stabilization, and invasive behavior (18,19), a complete picture of the underlying molecular mechanisms leading to chemoresistance remains to be elucidated. In this study, we reveal a signaling framework relevant for chemoresistance, providing evidence for a novel integration between ET A R/b-arr1 signaling and the b-catenin pathway, leading to chemoresistance onset.…”

“…Hence, ET A R and ET B R, which are heterogeneously expressed in EOC cells (14,15), have emerged as key targets for cancer therapy. A complex cross-talk between ET-1 signaling and other growth factor pathways drives tumor progression via the scaffold protein b-arrestin (b-arr, ARRB1) that serves as molecular hub to organize complex signaling network (16)(17)(18)(19). Some noteworthy cross-talk is the ET-1-mediated transactivation of receptor tyrosine kinases and b-catenin signaling (17,19).…”

Direct Action of Endothelin-1 on Podocytes Promotes Diabetic Glomerulosclerosis

“…It is well established that ET-1 can drive NF-kB and b-catenin pathway activation in several cell types; however, no information is available thus far regarding the downstream effectors of the ETR in podocytes. 10,[38][39][40][41] NF-kB was recently implicated in glomerular aging, by promoting inflammation, coagulation, and fibrosis. 56,57 A delicate balance of b-catenin expression in podocytes was recently demonstrated to be critical for podocyte cell adhesion and survival.…”

“…Because ETAR and ETBR can activate b-catenin and NF-kB pathways in nonglomerular cells, 10,[38][39][40][41] we analyzed the activation status of these pathways in glomeruli from Pod-ETRKO mice. We found that total b-catenin and phospho-NFkB expressions are reduced in glomeruli from Pod-ETRKO mice compared with WT mice in the basal state ( Figure 3, A and B).…”