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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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