학술논문
DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.
Document Type
article
Author
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
Source
Cancer cell. 28(1)
Subject
Language
Abstract
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.