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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, R Jeffrey;
- Takhar, Mandeep;
- Davicioni, Elai;
- Tomlins, Scott A;
- Abate-Shen, Cory;
- Sharifi, Nima;
- Witte, Owen N;
- Feng, Felix Y;
- Knudsen, Karen E
- et al.
Published Web Location
https://doi.org/10.1016/j.ccell.2015.06.004Abstract
Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo 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.
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