Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Bu, Huajie; Narisu, Narisu; Schlick, Bettina; Rainer, Johannes Michael; Manke, Thomas; Schäfer, Georg; Pasqualini, Lorenza; Chines, Peter S.; Schweiger, Michal R.; Fuchsberger, Christian; Klocker, Helmut

doi:10.1002/humu.22909

Cited by 36 publications

(31 citation statements)

References 75 publications

(124 reference statements)

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“…Specifically, the regulation has been observed to be SRF‐dependent, which relates to less than 6% of androgen‐regulated genes (Heemers et al, ). Interestingly, androgen treatment results in lower levels of DGAT2 (Ngan et al, ; Heemers et al, ; Rajan et al, ; Bu et al, ), which is similar to our finding of the association of the PrCa death‐associated alleles on the gene expression. Even though no AR binding cite exists on the location of the SNPs studied here (Lin et al, ; Massie et al, ), the effect of androgens could be mediated through an AR cooperator binding which the SNPs regulate.…”

Section: Discussionsupporting

confidence: 91%

“…The SNPs were not observed to affect the expression of DGAT2 in prostate tissue based on GTEx Portal, which further supports the role of DGAT2 in the later stage of malignant transformation rather than in the initiation of tumor development. Previously, DGAT2 has been identified in androgen-related studies as being an androgenregulated gene in PrCa cell lines (Lin et al, 2009;Ngan et al, 2009;Heemers et al, 2011;Rajan et al, 2011;Bu et al, 2016) and having an androgen receptor (AR) binding cite (Massie et al, 2011;Bu et al, 2016). Specifically, the regulation has been observed to be SRF-dependent, which relates to less than 6% of androgen-regulated genes (Heemers et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Expressional profiling of prostate cancer risk SNPs at 11q13.5 identifies DGAT2 as a new target gene

Nurminen

Rantapero

Wong

et al. 2016

Genes Chromosomes & Cancer

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A total of nine non-coding variants on 11q13.5 predispose men to prostate cancer (PrCa). rs200331695 within the EMSY intron is associated with aggressive PrCa and two high linkage disequilibrium (LD) groups of single-nucleotide polymorphisms (SNPs) in the intergenic region are associated with PrCa death. Here, the cis-effect of the SNPs on gene expression using expression quantitative trait loci analysis was investigated. The regulatory potential was screened in prostate tumors (n = 41) and in whole blood (n = 99). The results were validated in a second tumor set (n = 41), in lymphoblastoid cell lines (LCLs) (n = 38), and using the GTEx Portal. The effects of haplotypes were analyzed in the whole blood. The high LD SNPs (rs143975731, rs12277366, rs2155225, and rs2155222) were associated with DGAT2 expression in both tumors sets (screening P = 0.035-0.043; validation P = 0.005-0.018). The PrCa death-associated alleles decreased the expression by two-fold. rs200331695 decreased DGAT2 expression in LCLs (P = 0.006). The findings of SNPs regulating CAPN5 (P = 0.026-0.046) and AP001189.4 (P = 0.03-0.039) in the whole blood were not observed in LCLs, but the association with AP001189.4 expression was validated via the GTEx Portal (P = 8.7 × 10(-5) to 4.3 × 10(-4) ), which suggests that the high LD intergenic SNPs exert a tissue-dependent effect on the expression of two genes. No haplotypes including the risk SNPs at 11q13.5 were associated with gene expression and PrCa. The findings indicate the functionality of the PrCa death-predisposing SNPs rs143975731, rs12277366, rs2155225, and rs2155222 as DGAT2 regulators in prostate tumors. © 2016 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Expressional profiling of prostate cancer risk SNPs at 11q13.5 identifies DGAT2 as a new target gene

Nurminen

Rantapero

Wong

et al. 2016

Genes Chromosomes & Cancer

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“…Publicly available androgen receptor ChIP-Seq data from public datasets (GSE62442, GSE65478, and GSE70679; refs. 29,30) were analyzed in the UCSC browser. Detailed analysis was performed by calculating the coverage of aligned reads on 50-bp windows using bedtools (31).…”

Section: Analysis Of Public Bisulfite-seq and Androgen Receptor Chip-mentioning

confidence: 99%

“…Furthermore, inhibition of androgen receptor by enzalutamide was able to increase SOCS3 expression approximately 3-to 4-fold in the presence of different IL6 concentrations. To further investigate the mechanism of SOCS3 regulation by the androgen receptor, we screened for androgen receptor-binding sites in the SOCS3 gene using 12 published ChIP-Seq datasets (29,30). No androgen receptor-binding element could be found in the vicinity of the transcription start site of SOCS3 ( Supplementary Fig.…”

Section: Socs3 Is Expressed In Androgen Receptor-positive Prostate Camentioning

confidence: 99%

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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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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“…Moreover, a detailed investigation of AR-binding sites identified in the LNCaP-AR dataset revealed that most of these sites are predicted to contain ARE motifs. (Stelloo et al 2015, Bu et al 2016 (Supplementary Fig. 5).…”

Section: Ar Is a Direct Regulator Of Prkd1 Expressionmentioning

confidence: 99%

The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

Luef

Handle

Kharaishvili

et al. 2016

Endocrine-Related Cancer

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Due to the urgent need for new prostate cancer (PCa) therapies, the role of androgen receptor (AR)-interacting proteins should be investigated. In this study we aimed to address whether the AR coactivator nuclear receptor coactivator 1 (NCOA1) is involved in PCa progression. Therefore, we tested the effect of long-term NCOA1 knockdown on processes relevant to metastasis formation. [ 3 H]-thymidine incorporation assays revealed a reduced proliferation rate in AR-positive MDA PCa 2b and LNCaP cells upon knockdown of NCOA1, whereas AR-negative PC3 cells were not affected. Furthermore, Boyden chamber assays showed a strong decrease in migration and invasion upon NCOA1 knockdown, independently of the cell line's AR status. In order to understand the mechanistic reasons for these changes, transcriptome analysis using cDNA microarrays was performed. Protein kinase D1 (PRKD1) was found to be prominently up-regulated by NCOA1 knockdown in MDA PCa 2b, but not in PC3 cells. Inhibition of PRKD1 reverted the reduced migratory potential caused by NCOA1 knockdown. Furthermore, PRKD1 was negatively regulated by AR. Immunohistochemical staining of PCa patient samples revealed a strong increase in NCOA1 expression in primary tumors compared with normal prostate tissue, while no final conclusion could be drawn for PRKD1 expression in tumor specimens. Thus, our findings directly associate the AR/NCOA1 complex with PRKD1 regulation and cellular migration and support the concept of therapeutic inhibition of NCOA1 in PCa.

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Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

Cited by 36 publications

References 75 publications

Expressional profiling of prostate cancer risk SNPs at 11q13.5 identifies DGAT2 as a new target gene

Expressional profiling of prostate cancer risk SNPs at 11q13.5 identifies DGAT2 as a new target gene

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

The AR/NCOA1 axis regulates prostate cancer migration by involvement of PRKD1

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