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

  • Author(s): Goodwin, JF
  • Kothari, V
  • Drake, JM
  • Zhao, S
  • Dylgjeri, E
  • Dean, JL
  • Schiewer, MJ
  • McNair, C
  • Jones, JK
  • Aytes, A
  • Magee, MS
  • Snook, AE
  • Zhu, Z
  • Den, RB
  • Birbe, RC
  • Gomella, LG
  • Graham, NA
  • Vashisht, AA
  • Wohlschlegel, JA
  • Graeber, TG
  • Karnes, RJ
  • Takhar, M
  • Davicioni, E
  • Tomlins, SA
  • Abate-Shen, C
  • Sharifi, N
  • Witte, ON
  • Feng, FY
  • Knudsen, KE
  • et al.
Abstract

© 2015 Elsevier Inc.. Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, invitro and invivo 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. Goodwin etal. identify DNA-PKcs as a promising therapeutic target that drives prostate cancer progression and metastasis through transcriptional regulation. DNA-PKcs is significantly elevated in advanced disease and is an independent predictor of metastasis, recurrence, and poor survival.

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