Epigenetic silencing of <i>SOCS3</i> identifies a subset of prostate cancer with an aggressive behavior

Pierconti, Francesco; Martini, Maurizio; Pinto, Francesco; Cenci, Tonia; Capodimonti, Sara; Calarco, Alessandro; Bassi, Pier Francesco; Larocca, Luigi Maria

doi:10.1002/pros.21245

Cited by 68 publications

(54 citation statements)

References 31 publications

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“…The SOCS3 promoter region is frequently hypermethylated in prostate cancer patients Epigenetic regulation of SOCS3 expression by promoter hypermethylation has been reported in a variety of cancer types, including prostate cancer and it has been correlated with reduced SOCS3 mRNA expression (21)(22)(23). The SOCS3 gene contains a CpG island in the published promoter region of SOCS3 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Methylation-positive tissue samples were shown to have 4-to 7-fold lower SOCS3 mRNA expression levels (21)(22)(23), and use of a DNA methyltransferase inhibitor can increase SOCS3 mRNA expression in prostate cancer cell lines. This demonstrates a robust epigenetic regulation of SOCS3 expression.…”

Section: Discussionmentioning

confidence: 99%

“…This demonstrates a robust epigenetic regulation of SOCS3 expression. Previously, Pierconti and colleagues detected SOCS3 promoter hypermethylation in 39.2% of analyzed prostate cancer tissues, and an increased methylation was associated with higher Gleason score, tumor stage, and reduced progression-free survival (21). Because of this, the group proposed SOCS3 promoter methylation as a potential biomarker to identify more aggressive prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Previous publications could show that SOCS3 is an essential survival factor in androgen receptor-negative prostate cancer cell lines with an autocrine IL6 loop and that its RNAi-mediated knockdown led to cell death (20). In contrast to this, several publications could demonstrate that SOCS3 is frequently inactivated by promoter hypermethylation in different types of cancer, including prostate cancer (21)(22)(23). In addition, homozygous deletion of SOCS3 in a murine pancreatic intraepithelial neoplasia model led to accelerated cancer progression and reduced survival (24).…”

Section: Introductionmentioning

confidence: 99%

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SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

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Erb

Luef

et al. 2016

Molecular Cancer Research

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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.Implications: 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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Handle

Erb

Luef

et al. 2016

Molecular Cancer Research

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“…On one hand, overexpression of SOCS3 in DCs increases the proliferation of autoreactive Th cells in an EAE model (83), and transgenic mice overexpressing Socs3 show multiple features of asthma (84). In addition, preclinical observations unveil a relationship between SOCS3 overexpression in tumor cells and in vivo tumor growth inhibition (85,86). On the other hand, injection of autoantigenpulsed Socs3-transduced DCs suppresses the development of EAE (87), and splenic APCs overexpressing Socs3 prevent the development of collagen-induced arthritis (88).…”

Section: Socs3 An Inducer Of Ido Proteasomal Degradationmentioning

confidence: 99%

Different Partners, Opposite Outcomes: A New Perspective of the Immunobiology of Indoleamine 2,3-Dioxygenase

Orabona

Pallotta

Grohmann

2012

Mol Med

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Indoleamine 2,3-dioxygenase (IDO), a metabolic enzyme that catalyzes tryptophan conversion into kynurenines, is a crucial regulator of immunity. Altered IDO activity is often associated with pathology, including neoplasia and autoimmunity. IDO is highly expressed in dendritic cells (DCs) that exploit the enzyme's activity and the production of tryptophan catabolites to regulate immune responses by acting on several cell types, including T lymphocytes, of which they promote a regulatory phenotype. IDO also contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that, once bound by distinct molecular partners, will either promote degradation or initiate signaling activity and self-maintenance of the enzyme. We here discuss how ITIM-dependent molecular events can affect the functional plasticity of IDO by modifying the protein half-life and its enzymic and non enzymic functions.

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Identification of an aggressive prostate cancer predisposing variant at 11q13

Nurminen

Wahlfors

Tammela

et al. 2011

Intl Journal of Cancer

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Prostate cancer is the most frequently diagnosed cancer in men; however, the genetic basis of susceptibility remains elusive. The EMSY gene is located in the prostate cancer linked chromosome region at 11q13.5. The aim of this study was to screen EMSY for sequence variants and to evaluate its association with the risk of prostate cancer. We performed a Finnish population-based case-control study with 923 controls, 184 familial prostate cancer cases and 2,301 unselected prostate cancer cases. Variants were screened using sequencing and validated using the TaqMan assay and High Resolution Melting analysis. A total of 27 sequence variants were found, and 17 of them were novel. A rare intronic variant, IVS6-43A>G (minor allele frequency of 0.004), increased the prostate cancer risk in familial cases (odds ratio [OR] 5 7.5; 95% confidence interval [CI] 5 1.3-45.5; p 5 0.02). Further analysis with clinicopathological data revealed that the variant is associated with aggressive unselected cases (prostate specific antigen ! 20 lg/L or Gleason grade ! 7), based on both case-control (OR 5 6.0; 95% CI 5 1.3-26.4; p 5 0.03) and case-case analyses (OR 5 6.5; 95% CI 5 1.5-28.4; p 5 0.002). In addition, all variant-positive familial cases had aggressive cancer. Our results indicate that the intronic variant IVS6-43A>G increases the familial and unselected prostate cancer risk in a Finnish population and contributes to the aggressive progression of the disease in a high-penetrance manner. The potential role of the variant as a predictive genetic marker for aggressive prostate cancer should be further evaluated.

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Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior

Abstract: Our data suggest that SOCS3 hypermethylation may be involved in the pathogenesis of prostate cancer and could identify a tumor subset with an aggressive behavior.

Cited by 68 publications

References 31 publications

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

SOCS3 Modulates the Response to Enzalutamide and Is Regulated by Androgen Receptor Signaling and CpG Methylation in Prostate Cancer Cells

Different Partners, Opposite Outcomes: A New Perspective of the Immunobiology of Indoleamine 2,3-Dioxygenase

Identification of an aggressive prostate cancer predisposing variant at 11q13

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