Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling

Disharee Nath, Xiang Li, Claudia Mondragon, Dawn Post, Ming Chen, Julie R. White, Anita Hryniewicz-Jankowska, Tiffany Caza, Vladimir A. Kuznetsov, Heidi Hehnly, Tamara Jamaspishvili, David M. Berman, Fan Zhang, Sonia H.Y. Kung, Ladan Fazli, Martin E. Gleave, Gennady Bratslavsky, Pier Paolo Pandolfi, Leszek Kotula

Research output: Contribution to journalArticle

Abstract

Background: 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. 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. Methods: To 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. Results: Low 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. Conclusions: ABI1 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.

Original languageEnglish (US)
Article number120
JournalCell Communication and Signaling
Volume17
Issue number1
DOIs
StatePublished - Sep 18 2019

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Epithelial-Mesenchymal Transition
Tumors
Prostate
Carcinogenesis
Chemical activation
RNA Sequence Analysis
Cells
Neoplasms
Cell Line
Prostatic Neoplasms
Organoids
Phenotype
Genes
Association reactions
RNA
src Homology Domains
Phosphorylation
Tumor Cell Line
Actin Cytoskeleton
Cell Adhesion

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling. / Nath, Disharee; Li, Xiang; Mondragon, Claudia; Post, Dawn; Chen, Ming; White, Julie R.; Hryniewicz-Jankowska, Anita; Caza, Tiffany; Kuznetsov, Vladimir A.; Hehnly, Heidi; Jamaspishvili, Tamara; Berman, David M.; Zhang, Fan; Kung, Sonia H.Y.; Fazli, Ladan; Gleave, Martin E.; Bratslavsky, Gennady; Pandolfi, Pier Paolo; Kotula, Leszek.

In: Cell Communication and Signaling, Vol. 17, No. 1, 120, 18.09.2019.

Research output: Contribution to journalArticle

Nath, D, Li, X, Mondragon, C, Post, D, Chen, M, White, JR, Hryniewicz-Jankowska, A, Caza, T, Kuznetsov, VA, Hehnly, H, Jamaspishvili, T, Berman, DM, Zhang, F, Kung, SHY, Fazli, L, Gleave, ME, Bratslavsky, G, Pandolfi, PP & Kotula, L 2019, 'Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling', Cell Communication and Signaling, vol. 17, no. 1, 120. https://doi.org/10.1186/s12964-019-0410-y
Nath, Disharee ; Li, Xiang ; Mondragon, Claudia ; Post, Dawn ; Chen, Ming ; White, Julie R. ; Hryniewicz-Jankowska, Anita ; Caza, Tiffany ; Kuznetsov, Vladimir A. ; Hehnly, Heidi ; Jamaspishvili, Tamara ; Berman, David M. ; Zhang, Fan ; Kung, Sonia H.Y. ; Fazli, Ladan ; Gleave, Martin E. ; Bratslavsky, Gennady ; Pandolfi, Pier Paolo ; Kotula, Leszek. / Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling. In: Cell Communication and Signaling. 2019 ; Vol. 17, No. 1.
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AU - Li, Xiang

AU - Mondragon, Claudia

AU - Post, Dawn

AU - Chen, Ming

AU - White, Julie R.

AU - Hryniewicz-Jankowska, Anita

AU - Caza, Tiffany

AU - Kuznetsov, Vladimir A.

AU - Hehnly, Heidi

AU - Jamaspishvili, Tamara

AU - Berman, David M.

AU - Zhang, Fan

AU - Kung, Sonia H.Y.

AU - Fazli, Ladan

AU - Gleave, Martin E.

AU - Bratslavsky, Gennady

AU - Pandolfi, Pier Paolo

AU - Kotula, Leszek

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N2 - Background: 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. 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. Methods: To 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. Results: Low 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. Conclusions: ABI1 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.

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