DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

Jonathan F Goodwin; Vishal Kothari; Justin M Drake; Shuang Zhao; Emanuela Dylgjeri; Jeffry L Dean; Matthew J Schiewer; Christopher McNair; Jennifer K Jones; Alvaro Aytes; Michael S Magee; Adam E Snook; Ziqi Zhu; Robert B Den; Ruth C Birbe; Leonard G Gomella; Nicholas A Graham; Ajay A Vashisht; James A Wohlschlegel; Thomas G Graeber; R Jeffrey Karnes; Mandeep Takhar; Elai Davicioni; Scott A Tomlins; Cory Abate-Shen; Nima Sharifi; Owen N Witte; Felix Y Feng; Karen E Knudsen

doi:10.1016/j.ccell.2015.06.004

DNA-PKcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression and Metastasis

Cancer Cell. 2015 Jul 13;28(1):97-113. doi: 10.1016/j.ccell.2015.06.004.

Authors

Jonathan F Goodwin¹, Vishal Kothari², Justin M Drake³, Shuang Zhao², Emanuela Dylgjeri¹, Jeffry L Dean¹, Matthew J Schiewer¹, Christopher McNair¹, Jennifer K Jones¹, Alvaro Aytes⁴, Michael S Magee⁵, Adam E Snook⁵, Ziqi Zhu⁶, Robert B Den⁷, Ruth C Birbe⁸, Leonard G Gomella⁹, Nicholas A Graham¹⁰, Ajay A Vashisht¹¹, James A Wohlschlegel¹¹, Thomas G Graeber¹², R Jeffrey Karnes¹³, Mandeep Takhar¹⁴, Elai Davicioni¹⁴, Scott A Tomlins¹⁵, Cory Abate-Shen⁴, Nima Sharifi¹⁶, Owen N Witte¹⁷, Felix Y Feng¹⁸, Karen E Knudsen¹⁹

Affiliations

¹ Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
² Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Departments of Microbiology, Immunology, & Molecular Genetics, UCLA, Los Angeles, CA 90095, USA.
⁴ 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.
⁵ Department of Pharmacology & Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
⁶ Department of Cancer Biology, Cleveland Clinic, Cleveland, OH 44195, USA.
⁷ 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.
⁸ Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
⁹ Department of Urology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
¹⁰ Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA; Department of Molecular & Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA.
¹¹ Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA.
¹² 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.
¹³ Department of Urology, Mayo Clinic, Rochester, MN 55902, USA.
¹⁴ GenomeDx Biosciences, San Diego, CA 92121, USA.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line, Tumor
DNA-Activated Protein Kinase / genetics*
DNA-Activated Protein Kinase / metabolism*
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism*
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Humans
Male
Mice
Molecular Sequence Data
Neoplasm Invasiveness
Neoplasm Transplantation
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism*
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology*
Receptors, Androgen / genetics
Receptors, Androgen / metabolism

Substances

AR protein, human
DNA-Binding Proteins
Nuclear Proteins
Receptors, Androgen
DNA-Activated Protein Kinase
Prkdc protein, mouse

Associated data

GEO/GSE63480

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding