title: DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis.
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.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Goodwin
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Kothari
authors.affiliation: Departments of Microbiology, Immunology, & Molecular Genetics, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Drake
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Dylgjeri
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jeffry L
authors.initials: JL
authors.lastname: Dean
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schiewer
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: McNair
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Jones
authors.affiliation: Departments of Urology, Pathology & Cell Biology, Systems Biology, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Aytes
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Magee
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Snook
authors.affiliation: Department of Cancer Biology, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Ziqi
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Birbe
authors.affiliation: Department of Urology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.affiliation: Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Graham
authors.affiliation: Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Ajay A
authors.initials: AA
authors.lastname: Vashisht
authors.affiliation: Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Wohlschlegel
authors.affiliation: Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA; California NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN 55902, USA.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: GenomeDx Biosciences, San Diego, CA 92121, USA.
authors.forename: Mandeep
authors.initials: M
authors.lastname: Takhar
authors.affiliation: GenomeDx Biosciences, San Diego, CA 92121, USA.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Departments of Urology, Pathology & Cell Biology, Systems Biology, Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Abate-Shen
authors.affiliation: Department of Cancer Biology, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Urology, Cleveland Clinic, Cleveland, OH 44195, USA; Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Sharifi
authors.affiliation: Departments of Microbiology, Immunology, & Molecular Genetics, UCLA, Los Angeles, CA 90095, USA; Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, UCLA, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Urology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: karen.knudsen@jefferson.edu.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051747:DNA-Activated Protein Kinase / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
chemical_list: C410798:AR protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse