PBK promotes aggressive behavior of prostate cancer cells through upregulation of a β-catenin/TCF/LEF- and MYC-driven pro-metastasis gene expression program
Brown-Clay, Joshua Don
Banerjee, Partha P
A key question in prostate cancer research is how to distinguish aggressive prostate cancer from indolent neoplasms. Early treatment of aggressive cancers is essential to maximize therapeutic potential but treatment carries significant health risks and the majority of men diagnosed with prostate cancer will not die from the disease. Predictive nomograms have been developed to assess the risk of malignant progression but they are currently not robust enough to accurately recommend patients for therapy or surveillance. Biomarkers of aggressive prostate cancer are therefore urgently sought. This project aimed to evaluate the role of PDZ domain-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) in prostate cancer and to determine if PBK expression contributes to aggressive behavior of prostate cancer cells. Ectopic overexpression of PBK up-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 β-catenin-TCF/LEF signaling. Genetic knockdown or pharmacological inhibition of PBK function in aggressive prostate cancer cells caused reduced invasiveness and down-regulation of metalloproteinase production. We also demonstrated that PBK increases expression and transcription of the metastasis-promoting gene RANKL. This effect is mediated through PBK activity-dependent stabilization and β-catenin/TCF/LEF-induced transcription of the oncogenic transcription factor c-Myc. Analysis of human prostate cancer bone metastasis samples reveals significantly higher co-expression of PBK, MYC and RANKL, compared to non-tumor prostate and localized cancer patient samples. Finally, analysis of a large set of human prostate cancer samples and multiple, independent prostate cancer datasets revealed that PBK levels and nuclear localization are significantly associated with shorter recurrence-free survival, stage, grade and distant metastasis. 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 also a potential target for the therapeutic intervention of aggressive prostate cancer in men.
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