Abstract
BackgroundProstate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, acts as tumor suppressor in prostate cancer but the role of ABI1 in EMT is not clear.MethodsTo investigate the molecular mechanism by which loss of ABI1 contributes to tumor progression, we disrupted the ABI1 gene in the benign prostate epithelial RWPE-1 cell line and determined its phenotype. Levels of ABI1 expression in prostate organoid tumor cell lines was evaluated by Western blotting and RNA sequencing. ABI1 expression and its association with prostate tumor grade was evaluated in a TMA cohort of 505 patients and metastatic cell lines.ResultsLow ABI1 expression is associated with biochemical recurrence, metastasis and death (p = 0.038). Moreover, ABI1 expression was significantly decreased in Gleason pattern 5 vs. pattern 4 (p = 0.0025) and 3 (p = 0.0012), indicating an association between low ABI1 expression and highly invasive prostate tumors. Disruption of ABI1 gene in RWPE-1 cell line resulted in gain of an invasive phenotype, which was characterized by a loss of cell-cell adhesion markers and increased migratory ability of RWPE-1 spheroids. Through RNA sequencing and protein expression analysis, we discovered that ABI1 loss leads to activation of non-canonical WNT signaling and EMT pathways, which are rescued by re-expression of ABI1. Furthermore, an increase in STAT3 phosphorylation upon ABI1 inactivation and the evidence of a high-affinity interaction between the FYN SH2 domain and ABI1 pY421 support a model in which ABI1 acts as a gatekeeper of non-canonical WNT-EMT pathway activation downstream of the FZD2 receptor.ConclusionsABI1 controls prostate tumor progression and epithelial plasticity through regulation of EMT-WNT pathway. Here we discovered that ABI1 inhibits EMT through suppressing FYN-STAT3 activation downstream from non-canonical WNT signaling thus providing a novel mechanism of prostate tumor suppression.
Highlights
Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease
Low Abi1 expression is associated with high-grade prostate cancer and biochemical recurrence Our previous studies identified the loss of heterozygosity in ABI1 gene locus [37], the mechanism of ABI1 role as a tumor suppressor in prostate cancer is poorly understood
Staining of a test tumor tissue microarray (32 cases) with ABI1 antibody demonstrated a remarkable loss of ABI1 expression in tumors with high Gleason grade (Additional file 1: Figure S1A)
Summary
Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease. While indolent PCa is treatable, metastatic cancer invariably has a high mortality rate [2], warranting studies of PCa progression mechanisms and development of new therapeutic targets. Several growth control pathways have been implicated in high-risk prostate cancer. Aggressive prostate cancer has been linked to Androgen Receptor (AR) activation, which occurs through multiple mechanisms, including intra-tumor androgen production [4]. Bioinformatic inquiries over the last decade have resulted in a better understanding of signaling pathways and genetic alterations associated with prostate cancer initiation [7] and metastatic progression [8, 9]. Our previous studies implicated ABI1 downregulation in high-risk prostate tumors [10], but the mechanism underlying Abi tumor suppressor activity is unclear
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