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.
Bibliographical noteFunding Information:
The authors thank Dr. A. Fatatis and T.J. Stanek for reagents, and N. Erho (GenomeDx) and members of the K.E.K. laboratory for input. This work was supported by grants from PCF (to M.J.S.); PCF/Movember and Evans Foundation (to F.Y.F., S.A.T., and K.E.K.); PA CURE and NCI CA159945, CA176401 (to K.E.K.); DOD PCa Research program W81XWH-14-1-0148 (to J.M.D.); UCLA SOMI and NIH R25T CA098010 (to N.A.G.); NIH GM089778 (to J.A.W.); NCI CA168585 and ACS RSG-12-257-01-TBE (to T.G.G.); NCATS UCLA UL1TR000124 (to T.G.G. and O.N.W.); PCF (to O.N.W.); and NCI CA173481, CA183929 (to C.A.-S.). O.N.W. is an Investigator of the Howard Hughes Medical Institute and partially supported by a Stand Up to Cancer-PCF-Prostate Dream Team Translational Cancer Research Grant (co-PI), a grant made possible through the Movember Foundation. Stand Up to Cancer is a program of the Entertainment Industry Foundation administered by AACR. K.E.K. receives research support from Celgene.
© 2015 Elsevier Inc..