SOCS3 Modulates the Response to Enzalutamide and is Regulated by AR Signaling and CpG Methylation in Prostate Cancer Cells

The pro-inflammatory cytokine interleukin 6 (IL6) is associated with bad prognosis in prostate cancer (PCa) 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)/signal transducer and activator of transcription 3 (STAT3) pathway.

This study reveals that the SOCS3 promoter is hypermethylated in cancerous regions compared to adjacent benign tissue in PCa using methylation-specific qPCR. A series of in vitro experiments were 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 (AR) positive LNCaP cells. Additionally, SOCS3 mRNA is up-regulated by the anti-androgens bicalutamide and enzalutamide. This effect is caused by AR mediated suppression of IL6ST and JAK1 expression, which leads to altered STAT3 signaling. Functionally, knockdown of SOCS3 led to enhanced AR activity after three weeks of enzalutamide treatment in an inflammatory setting. Furthermore, the stemness/self-renewal associated genes SOX2 and NANOG were strongly up-regulated 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.

IMPLICATIONS - SOCS3 is frequently inactivated by promoter hypermethylation in PCa, which disrupts the feedback regulation of IL6 signaling and leads to reduced efficacy of enzalutamide in the presence of inflammatory cytokines.

Molecular cancer research : MCR. 2016 Apr 06 [Epub ahead of print]

Florian Handle, Holger H H Erb, Birgit Luef, Julia Hoefer, Dimo Dietrich, Walther Parson, Glen Kristiansen, Frederic R Santer, Zoran Culig

Division of Experimental Urology, Department of Urology, Medical University of Innsbruck., Yorkshire Cancer Research Unit, University of York., Division of Experimental Urology, Department of Urology, Medical University of Innsbruck., Division of Experimental Urology, Department of Urology, Medical University of Innsbruck., Institute of Pathology, University Hospital Bonn., Institute of Legal Medicine, Medical University of Innsbruck., Forensic Science Program, The Pennsylvania State University., Division of Experimental Urology, Department of Urology, Medical University of Innsbruck., Division of Experimental Urology, Department of Urology, Medical University of Innsbruck  

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