title: SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells.
abstract: The proinflammatory cytokine IL6 is associated with bad prognosis in prostate cancer and implicated in progression to castration resistance. Suppressor of cytokine signaling 3 (SOCS3) is an IL6-induced negative feedback regulator of the IL6/Janus kinase (JAK)/STAT3 pathway. This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared with adjacent benign tissue in prostate cancer using methylation-specific qPCR. A series of in vitro experiments was performed to assess the functional impact of low SOCS3 expression during anti-androgen treatment. Using lentivirus-mediated knockdown, it was demonstrated for the first time that SOCS3 regulates IL6/JAK/STAT3 signaling in androgen receptor-positive LNCaP cells. In addition, SOCS3 mRNA is upregulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by androgen receptor-mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced androgen receptor activity after 3 weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly upregulated by the long-term treatment, and modulation of SOCS3 expression was sufficient to counteract this effect. These findings prove that SOCS3 plays an important role during anti-androgen treatment in an inflammatory environment.
  
  
  
  SOCS3 is frequently inactivated by promoter hypermethylation in prostate cancer, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines. Mol Cancer Res; 14(6); 574-85. ©2016 AACR.
authors.affiliation: Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Handle
authors.affiliation: Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria. Yorkshire Cancer Research Unit, University of York, York, United Kingdom.
authors.forename: Holger H H
authors.initials: HH
authors.lastname: Erb
authors.affiliation: Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Luef
authors.affiliation: Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefer
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.affiliation: Institute of Legal Medicine, Medical University of Innsbruck, Innsbruck, Austria. Forensic Science Program, The Pennsylvania State University, University Park, Pennsylvania.
authors.forename: Walther
authors.initials: W
authors.lastname: Parson
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria. zoran.culig@i-med.ac.at frederic.santer@i-med.ac.at.
authors.forename: Frédéric R
authors.initials: FR
authors.lastname: Santer
authors.affiliation: Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria. zoran.culig@i-med.ac.at frederic.santer@i-med.ac.at.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Culig
mesh_terms: D001549:Benzamides; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D057809:HEK293 Cells; D006801:Humans; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: C410798:AR protein, human; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D010669:Phenylthiohydantoin; C540278:enzalutamide; D053612:Janus Kinases