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.
Recommended CitationGoodwin, 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; 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.; and Knudsen, Karen E., "DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis." (2015). Department of Cancer Biology Faculty Papers. Paper 92.
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