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

72 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

Cite this

Goodwin, J., Kothari, V., Drake, J., Zhao, S., Dylgjeri, E., Dean, 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

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. / Goodwin, JonathanF; Kothari, Vishal; Drake, JustinM; Zhao, Shuang; Dylgjeri, Emanuela; Dean, JeffryL; Schiewer, MatthewJ; McNair, Christopher; Jones, JenniferK; Aytes, Alvaro; Magee, MichaelS; Snook, AdamE; Zhu, Ziqi; Den, RobertB; Birbe, RuthC; Gomella, LeonardG; Graham, NicholasA; Vashisht, AjayA; Wohlschlegel, JamesA; Graeber, ThomasG; Karnes, R. Jeffrey; Takhar, Mandeep; Davicioni, Elai; Tomlins, ScottA; Abate-Shen, Cory; Sharifi, Nima; Witte, OwenN; Feng, FelixY; Knudsen, KarenE.

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

Research output: Contribution to journalArticle

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, Graeber, T, Karnes, RJ, Takhar, M, Davicioni, E, Tomlins, S, Abate-Shen, C, Sharifi, N, Witte, O, Feng, F & Knudsen, K 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, JonathanF ; Kothari, Vishal ; Drake, JustinM ; Zhao, Shuang ; Dylgjeri, Emanuela ; Dean, JeffryL ; Schiewer, MatthewJ ; McNair, Christopher ; Jones, JenniferK ; Aytes, Alvaro ; Magee, MichaelS ; Snook, AdamE ; Zhu, Ziqi ; Den, RobertB ; Birbe, RuthC ; Gomella, LeonardG ; Graham, NicholasA ; Vashisht, AjayA ; Wohlschlegel, JamesA ; Graeber, ThomasG ; Karnes, R. Jeffrey ; Takhar, Mandeep ; Davicioni, Elai ; Tomlins, ScottA ; Abate-Shen, Cory ; Sharifi, Nima ; Witte, OwenN ; Feng, FelixY ; Knudsen, KarenE. / DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis. In: Cancer Cell. 2015 ; Vol. 28, No. 1. pp. 97-113.
@article{fddbc7c90b1b48d488186b16c0c21e4a,
title = "DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis",
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.",
author = "JonathanF Goodwin and Vishal Kothari and JustinM Drake and Shuang Zhao and Emanuela Dylgjeri and JeffryL Dean and MatthewJ Schiewer and Christopher McNair and JenniferK Jones and Alvaro Aytes and MichaelS Magee and AdamE Snook and Ziqi Zhu and RobertB Den and RuthC Birbe and LeonardG Gomella and NicholasA Graham and AjayA Vashisht and JamesA Wohlschlegel and ThomasG Graeber and Karnes, {R. Jeffrey} and Mandeep Takhar and Elai Davicioni and ScottA Tomlins and Cory Abate-Shen and Nima Sharifi and OwenN Witte and FelixY Feng and KarenE Knudsen",
year = "2015",
month = "7",
day = "13",
doi = "10.1016/j.ccell.2015.06.004",
language = "English (US)",
volume = "28",
pages = "97--113",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

AU - Goodwin, JonathanF

AU - Kothari, Vishal

AU - Drake, JustinM

AU - Zhao, Shuang

AU - Dylgjeri, Emanuela

AU - Dean, JeffryL

AU - Schiewer, MatthewJ

AU - McNair, Christopher

AU - Jones, JenniferK

AU - Aytes, Alvaro

AU - Magee, MichaelS

AU - Snook, AdamE

AU - Zhu, Ziqi

AU - Den, RobertB

AU - Birbe, RuthC

AU - Gomella, LeonardG

AU - Graham, NicholasA

AU - Vashisht, AjayA

AU - Wohlschlegel, JamesA

AU - Graeber, ThomasG

AU - Karnes, R. Jeffrey

AU - Takhar, Mandeep

AU - Davicioni, Elai

AU - Tomlins, ScottA

AU - Abate-Shen, Cory

AU - Sharifi, Nima

AU - Witte, OwenN

AU - Feng, FelixY

AU - Knudsen, KarenE

PY - 2015/7/13

Y1 - 2015/7/13

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84937423115&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84937423115&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2015.06.004

DO - 10.1016/j.ccell.2015.06.004

M3 - Article

C2 - 26175416

AN - SCOPUS:84937423115

VL - 28

SP - 97

EP - 113

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 1

ER -