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

Publication ,  Journal Article
Nath, D; Li, X; Mondragon, C; Post, D; Chen, M; White, JR; Hryniewicz-Jankowska, A; Caza, T; Kuznetsov, VA; Hehnly, H; Jamaspishvili, T ...
Published in: Cell Commun Signal
September 18, 2019

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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Published In

Cell Commun Signal

DOI

EISSN

1478-811X

Publication Date

September 18, 2019

Volume

17

Issue

1

Start / End Page

120

Location

England

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Up-Regulation
  • STAT3 Transcription Factor
  • Recurrence
  • Prostatic Neoplasms
  • Phenotype
  • Neoplasm Grading
  • Male
  • Humans
 

Citation

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Nath, D., Li, X., Mondragon, C., Post, D., Chen, M., White, J. R., … Kotula, L. (2019). Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling. Cell Commun Signal, 17(1), 120. https://doi.org/10.1186/s12964-019-0410-y
Nath, Disharee, Xiang Li, Claudia Mondragon, Dawn Post, Ming Chen, Julie R. White, Anita Hryniewicz-Jankowska, et al. “Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling.Cell Commun Signal 17, no. 1 (September 18, 2019): 120. https://doi.org/10.1186/s12964-019-0410-y.
Nath D, Li X, Mondragon C, Post D, Chen M, White JR, et al. Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling. Cell Commun Signal. 2019 Sep 18;17(1):120.
Nath, Disharee, et al. “Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling.Cell Commun Signal, vol. 17, no. 1, Sept. 2019, p. 120. Pubmed, doi:10.1186/s12964-019-0410-y.
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. Abi1 loss drives prostate tumorigenesis through activation of EMT and non-canonical WNT signaling. Cell Commun Signal. 2019 Sep 18;17(1):120.
Journal cover image

Published In

Cell Commun Signal

DOI

EISSN

1478-811X

Publication Date

September 18, 2019

Volume

17

Issue

1

Start / End Page

120

Location

England

Related Subject Headings

  • beta Catenin
  • Wnt Signaling Pathway
  • Up-Regulation
  • STAT3 Transcription Factor
  • Recurrence
  • Prostatic Neoplasms
  • Phenotype
  • Neoplasm Grading
  • Male
  • Humans