title: Cyclin D1 Promotes Androgen-Dependent DNA Damage Repair in Prostate Cancer Cells.
abstract: Therapy resistance and poor outcome in prostate cancer is associated with increased expression of cyclin D1. Androgens promote DNA double-strand break repair to reduce DNA damage, and cyclin D1 was also shown to enhance DNA damage repair (DDR). In this study, we investigated the significance of cyclin D1 in androgen-induced DDR using established prostate cancer cells and prostate tissues from cyclin D1 knockout mice. We demonstrate that endogenous cyclin D1 further diminished the dihydrotestosterone (DHT)-dependent reduction of γH2AX foci in vitro. We also show that cyclin D1 was required for the androgen-dependent DNA damage response both in vitro and in vivo. Furthermore, cyclin D1 was required for androgen-enhanced DDR and radioresistance of prostate cancer cells. Moreover, microarray analysis of primary prostate epithelial cells from cyclin D1-deficient and wild-type mice demonstrated that most of the DHT-dependent gene expression changes are also cyclin D1 dependent. Collectively, our findings suggest that the hormone-mediated recruitment of cyclin D1 to sites of DDR may facilitate the resistance of prostate cancer cells to DNA damage therapies and highlight the need to explore other therapeutic approaches in prostate cancer to prevent or overcome drug resistance.
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Di Sante
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ju
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Science and Technology, Tongji Hospital, Tongji Medical College, Huazhong University of Technology, Shanghai, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Marco
authors.initials: M
authors.lastname: Crosariol
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Ismail
authors.initials: I
authors.lastname: Yaman
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Gormley
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania. University of Manchester, Manchester Breast Center, Manchester, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania. Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania. Kazan Federal University, Kazan, Republic of Tatarstan, Russia. richard.pestell@jefferson.edu.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D013196:Dihydrotestosterone / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; C468783:H2AX protein, human; D006657:Histones; C475961:gamma-H2AX protein, mouse; D013196:Dihydrotestosterone; D019938:Cyclin D1