DNA-Dependent Protein Kinase Drives Prostate Cancer Progression through Transcriptional Regulation of the Wnt Signaling Pathway

• Published in: Clinical cancer research Vol. 25; no. 18; pp. 5608 - 5622
• Main Authors: Kothari, Vishal, Goodwin, Jonathan F, Zhao, Shuang G, Drake, Justin M, Yin, Yi, Chang, S Laura, Evans, Joseph R, Wilder-Romans, Kari, Gabbara, Kristina, Dylgjeri, Emanuela, Chou, Jonathan, Sun, Grace, Tomlins, Scott A, Mehra, Rohit, Hege, Kristen, Filvaroff, Ellen H, Schaeffer, Edward M, Karnes, R Jeffrey, Quigley, David A, Rathkopf, Dana E, He, Housheng H, Speers, Corey, Spratt, Daniel E, Gilbert, Luke A, Ashworth, Alan, Chinnaiyan, Arul M, Raj, Ganesh V, Knudsen, Karen E, Feng, Felix Y
• Format: Journal Article
• Language: English
• Published: United States 15-09-2019
• Subjects: Animals; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Disease Progression; DNA-Activated Protein Kinase - antagonists & inhibitors; DNA-Activated Protein Kinase - genetics; DNA-Activated Protein Kinase - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Heterografts; Humans; Male; Mice; Neoplasm Metastasis; Phenotype; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Protein Binding; RNA, Small Interfering - genetics; Transcription, Genetic; Wnt Signaling Pathway
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-2387

Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression.
To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression
and
.
DNA-dependent protein kinase (
) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of
suppressed the growth of both
-dependent and
-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with
. We found that
interacts with the Wnt transcription factor
and is critical for
-mediated transcription.
Our data show that
drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.