Dataset Information

PBK/TOPK enhances aggressive phenotype in prostate cancer via ?-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion.

ABSTRACT: A current challenge in prostate cancer treatment is how to differentiate aggressive disease from indolent prostate cancer. There is an urgent need to identify markers that would accurately distinguish indolent prostate cancer from aggressive disease. The aim of this study was to evaluate the role of PDZ Domain-binding kinase (PBK) in prostate cancer and to determine if PBK expression enhances aggressiveness in prostate cancer. Using archival tissue samples, gain-of-function and loss-of-function studies, we show that PBK expression is up-regulated in prostate cancer, and its expression level is commensurate with invasiveness. Modulation of PBK expression and function causally regulates the invasive ability of prostate cancer cells. Production of matrix metalloproteinases-2 and -9, which are key players in metastatic invasion, is up-regulated, and the promoters of these genes are transcriptionally activated by PBK via increased ?-catenin-TCF/LEF signaling. Prostate cancer tissue specimens show that PBK's expression correlates with aggressive disease and distant metastasis in bone, lymph node and abdomen. Our in vitro and in situ data are in agreement that PBK could be a prognostic biomarker for prostate cancer that would discriminate aggressive prostate cancer from indolent disease, and is a potential target for the therapeutic intervention of aggressive prostate cancer in men.

SUBMITTER: Brown-Clay JD

PROVIDER: S-EPMC4558173 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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PBK/TOPK enhances aggressive phenotype in prostate cancer via β-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion.

Brown-Clay Joshua D JD Shenoy Deepika N DN Timofeeva Olga O Kallakury Bhaskar V BV Nandi Asit K AK Banerjee Partha P PP

Oncotarget 20150601 17

A current challenge in prostate cancer treatment is how to differentiate aggressive disease from indolent prostate cancer. There is an urgent need to identify markers that would accurately distinguish indolent prostate cancer from aggressive disease. The aim of this study was to evaluate the role of PDZ Domain-binding kinase (PBK) in prostate cancer and to determine if PBK expression enhances aggressiveness in prostate cancer. Using archival tissue samples, gain-of-function and loss-of-function ...[more]

PMID: 25909225

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Project description:The canonical Wnt signaling pathway is mediated by interaction of β-catenin with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors and subsequent transcription activation of Wnt-target genes. In the hematopoietic system, the function of the pathway has been mainly investigated by rather unspecific genetic manipulations of β-catenin that yielded contradictory results. Here, we used a mouse expressing a truncated dominant negative form of the human TCF4 transcription factor (dnTCF4) that specifically abrogates β-catenin-TCF/LEF interaction. Disruption of the β-catenin-TCF/LEF interaction resulted in the accumulation of immature cells and reduced granulocytic differentiation. Mechanistically, dnTCF4 progenitors exhibited downregulation of the Csf3r gene, reduced granulocyte colony-stimulating factor (G-CSF) receptor levels, attenuation of downstream Stat3 phosphorylation after G-CSF treatment, and impaired G-CSF-mediated differentiation. Chromatin immunoprecipitation assays confirmed direct binding of TCF/LEF factors to the promoter and putative enhancer regions of CSF3R. Inhibition of β-catenin signaling compromised activation of the emergency granulopoiesis program, which requires maintenance and expansion of myeloid progenitors. Consequently, dnTCF4 mice were more susceptible to Candida albicans infection and more sensitive to 5-fluorouracil-induced granulocytic regeneration. Importantly, genetic and chemical inhibition of β-catenin-TCF/LEF signaling in human CD34+ cells reduced granulocytic differentiation, whereas its activation enhanced myelopoiesis. Altogether, our data indicate that the β-catenin-TCF/LEF complex directly regulates G-CSF receptor levels, and consequently controls proper differentiation of myeloid progenitors into granulocytes in steady-state and emergency granulopoiesis. Our results uncover a role for the β-catenin signaling pathway in fine tuning the granulocytic production, opening venues for clinical intervention that require enhanced or reduced production of neutrophils.

Dataset Information

PBK/TOPK enhances aggressive phenotype in prostate cancer via ?-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion.

Publications

PBK/TOPK enhances aggressive phenotype in prostate cancer via β-catenin-TCF/LEF-mediated matrix metalloproteinases production and invasion.

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