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

JonathanF Goodwin, Vishal Kothari, JustinM Drake, Shuang Zhao, Emanuela Dylgjeri, JeffryL Dean, MatthewJ Schiewer, Christopher McNair, JenniferK Jones, Alvaro Aytes, MichaelS Magee, AdamE Snook, Ziqi Zhu, RobertB Den, RuthC Birbe, LeonardG Gomella, NicholasA Graham, AjayA Vashisht, JamesA Wohlschlegel, ThomasG GraeberR. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, ScottA Tomlins, Cory Abate-Shen, Nima Sharifi, OwenN Witte, FelixY Feng, KarenE Knudsen

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)97-113
Number of pages17
JournalCancer Cell
Volume28
Issue number1
DOIs
StatePublished - Jul 13 2015

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Goodwin, J., Kothari, V., Drake, J., Zhao, S., Dylgjeri, E., Dean, J., Schiewer, M., McNair, C., Jones, J., Aytes, A., Magee, M., Snook, A., Zhu, Z., Den, R., Birbe, R., Gomella, L., Graham, N., Vashisht, A., Wohlschlegel, J., ... Knudsen, K. (2015). DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. Cancer Cell, 28(1), 97-113. https://doi.org/10.1016/j.ccell.2015.06.004