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.
Published Web Location
https://doi.org/10.1016/j.ccell.2015.06.004Abstract
© 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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