title: Potential Role for YB-1 in Castration-Resistant Prostate Cancer and Resistance to Enzalutamide Through the Androgen Receptor V7.
abstract: BACKGROUND
  Although androgen deprivation therapy for advanced prostate cancer initially exerts excellent anticancer effects, most prostate cancer treated with androgen deprivation therapy eventually recurs as castration-resistant prostate cancer (CRPC). Although aberrant kinase activation has been proposed as a mechanism of castration resistance, comprehensive kinase profiles in CRPC remain unknown. Therefore, we aimed to elucidate the kinome in CRPC as well as the role of key molecules.
  
  
  METHODS
  We utilized a kinome array in androgen-dependent LNCaP and castration-resistant CxR cells. The effect of Y-box binding protein-1 (YB-1) on androgen receptor (AR) expression was examined by quantitative polymerase chain reaction and western blot analysis. The association between polymorphisms in the YB-1 gene determined by genotyping and YB-1 expression evaluated by immunohistochemistry in prostate cancer tissues, as well as outcome in metastatic prostate cancer, were investigated by the Cochran-Armitage test and the Cox proportional hazards model, respectively. All statistical tests were two-sided.
  
  
  RESULTS
  One hundred fifty-six of 180 kinase phosphorylation sites, including ERK and RSK, were activated in CRPC cells, leading to increased phosphorylation of YB-1, which is a key molecule in the progression to CRPC. YB-1 signaling regulated AR V7 expression, and YB-1 inhibition augmented the anticancer effect of enzalutamide. Moreover, polymorphism (rs12030724) in the YB-1 gene affected YB-1 expression in 93 prostate cancer tissues (YB-1 positive rate; 14.3% in TT, 40.0% in AT, and 52.9% in AA, P = .04) and associated with probability of progression in 104 metastatic prostate cancer case patients (AT/TT vs AA, hazard ratio = 0.49, 95% confidence interval = 0.32 to 0.77, P = .001).
  
  
  CONCLUSIONS
  YB-1 appears to be a promising target to inhibit the development of castration resistance, even at the AR variant-expressing stage. Polymorphism in the YB-1 gene may be a promising predictive biomarker in hormonal therapy.
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Masaki
authors: M
authors: Shiota
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Naohiro
authors: N
authors: Fujimoto
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Kenjiro
authors: K
authors: Imada
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Akira
authors: A
authors: Yokomizo
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Momoe
authors: M
authors: Itsumi
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Ario
authors: A
authors: Takeuchi
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Hidetoshi
authors: H
authors: Kuruma
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Junichi
authors: J
authors: Inokuchi
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Katsunori
authors: K
authors: Tatsugami
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Takeshi
authors: T
authors: Uchiumi
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Yoshinao
authors: Y
authors: Oda
authors: Affiliations of authors:Department of Urology (MS, KI, AY, MI, AT, JI, KT, SN), Department of Anatomic Pathology (KI, YO), and Department of Clinical Chemistry and Laboratory Medicine (TU), Graduate School of Medical Sciences, Kyushu University , Fukuoka , Japan ; Department of Urology, School of Medicine, University of Occupational and Environmental Health , Kitakyushu , Japan (NF); Department of Urology, School of Medicine, Jikei University , Tokyo , Japan (HK).
authors: Seiji
authors: S
authors: Naito
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D016017:Odds Ratio; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D010669:Phenylthiohydantoin; C540278:enzalutamide