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
N1 - Publisher Copyright:
© 2015 Elsevier Inc..
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.
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U2 - 10.1016/j.ccell.2015.06.004
DO - 10.1016/j.ccell.2015.06.004
M3 - Article
C2 - 26175416
AN - SCOPUS:84937423115
SN - 1535-6108
VL - 28
SP - 97
EP - 113
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -