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DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.

  • Author(s): Goodwin, Jonathan F
  • Kothari, Vishal
  • Drake, Justin M
  • Zhao, Shuang
  • Dylgjeri, Emanuela
  • Dean, Jeffry L
  • Schiewer, Matthew J
  • McNair, Christopher
  • Jones, Jennifer K
  • Aytes, Alvaro
  • Magee, Michael S
  • Snook, Adam E
  • Zhu, Ziqi
  • Den, Robert B
  • Birbe, Ruth C
  • Gomella, Leonard G
  • Graham, Nicholas A
  • Vashisht, Ajay A
  • Wohlschlegel, James A
  • Graeber, Thomas G
  • Karnes, R Jeffrey
  • Takhar, Mandeep
  • Davicioni, Elai
  • Tomlins, Scott A
  • Abate-Shen, Cory
  • Sharifi, Nima
  • Witte, Owen N
  • Feng, Felix Y
  • Knudsen, Karen E
  • et al.
Abstract

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies.

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