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

Clin Cancer Res. 2019 Sep 15;25(18):5608-5622. doi: 10.1158/1078-0432.CCR-18-2387. Epub 2019 Jul 2.


Purpose: 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.Experimental Design: 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 in vitro and in vivo.

Results: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription.

Conclusions: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cell Movement
  • DNA-Activated Protein Kinase / antagonists & inhibitors
  • DNA-Activated Protein Kinase / genetics
  • DNA-Activated Protein Kinase / metabolism*
  • Disease Models, Animal
  • Disease Progression
  • 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*


  • Biomarkers, Tumor
  • RNA, Small Interfering
  • DNA-Activated Protein Kinase