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

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

Research output: Contribution to journalArticle

70 Citations (Scopus)

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

Fingerprint

Prostatic Neoplasms
Neoplasm Metastasis
DNA
Neoplasms
Polynucleotide 5'-Hydroxyl-Kinase
Recurrence
Gene Regulatory Networks
DNA Repair
DNA Damage
Cell Movement
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology
  • Medicine(all)

Cite this

Goodwin, J. F., Kothari, V., Drake, J. M., Zhao, S., Dylgjeri, E., Dean, J. L., ... Knudsen, K. E. (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

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. / 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, Robert Jeffrey; Takhar, Mandeep; Davicioni, Elai; Tomlins, Scott A.; Abate-Shen, Cory; Sharifi, Nima; Witte, Owen N.; Feng, Felix Y.; Knudsen, Karen E.

In: Cancer Cell, Vol. 28, No. 1, 13.07.2015, p. 97-113.

Research output: Contribution to journalArticle

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 2015, 'DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis', Cancer Cell, vol. 28, no. 1, pp. 97-113. https://doi.org/10.1016/j.ccell.2015.06.004
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, Robert Jeffrey ; Takhar, Mandeep ; Davicioni, Elai ; Tomlins, Scott A. ; Abate-Shen, Cory ; Sharifi, Nima ; Witte, Owen N. ; Feng, Felix Y. ; Knudsen, Karen E. / DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. In: Cancer Cell. 2015 ; Vol. 28, No. 1. pp. 97-113.
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