title: EAF2 regulates DNA repair through Ku70/Ku80 in the prostate.
abstract: Androgens are known to protect prostate cancer cells from DNA damage. Recent studies showed regulation of DNA repair genes by androgen receptor signaling in prostate cancers. ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor and its intracellular localization can be modulated by ultraviolet light, suggesting a potential role for EAF2 in androgen regulation of DNA repair in prostate cancer cells. Here we show that knockdown of EAF2 or its homolog EAF1 sensitized prostate cancer cells to DNA damage and the sensitization did not require p53. EAF2 knockout mouse prostate was also sensitized to γ-irradiation. Furthermore, EAF2 knockdown blocked androgen repression of LNCaP or C4-2 cells from doxorubicin induction of γH2ax, a DNA damage marker. In human prostate cancer specimens, EAF2 expression was inversely correlated with the level of γH2ax. Further analysis showed that EAF2 and EAF1 are required for the recruitment and retention of Ku70/Ku80 to DNA damage sites and play a functional role in nonhomologous end-joining DNA repair. These findings provide evidence for EAF2 as a key factor mediating androgen protection of DNA damage via Ku70/Ku80 in prostate cancer cells.
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ai
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Pascal
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zang
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Cancer Center, Southern Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Urology, Peking University First Hospital and Institute of Urology, Peking University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Gong
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Nelson
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Levine
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lan
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D000728:Androgens; D000903:Antibiotics, Antineoplastic; C472771:EAF2 protein, human; D014157:Transcription Factors; D004317:Doxorubicin; D000072200:Ku Autoantigen