Androgen modulation of XBP1 is functionally driving part of the AR transcriptional program

in Endocrine-Related Cancer
Authors:
Suzan Stelloo Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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Simon Linder Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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Ekaterina Nevedomskaya Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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Eider Valle-Encinas Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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Iris de Rink Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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Lodewyk F A Wessels Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands

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Henk van der Poel Division of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

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Andries M Bergman Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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Wilbert Zwart Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands

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Correspondence should be addressed to A M Bergman or W Zwart: a.bergman@nki.nl or w.zwart@nki.nl

*(S Stelloo and S Linder contributed equally to this work)

DOI:
https://doi.org/10.1530/ERC-19-0181
Volume/Issue:
Volume 27: Issue 2
Article Type:
Research Article
Page Range:
67–79
Online Publication Date:
Feb 2020
Copyright:
© 2020 Society for Endocrinology 2020
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Prostate cancer development and progression is largely dependent on androgen receptor (AR) signaling. AR is a hormone-dependent transcription factor, which binds to thousands of sites throughout the human genome to regulate expression of directly responsive genes, including pro-survival genes that enable tumor cells to cope with increased cellular stress. ERN1 and XBP1 – two key players of the unfolded protein response (UPR) – are among such stress-associated genes. Here, we show that XBP1 levels in primary prostate cancer are associated with biochemical recurrence in five independent cohorts. Patients who received AR-targeted therapies had significantly lower XBP1 expression, whereas expression of the active form of XBP1 (XBP1s) was elevated. In vitro results show that AR-induced ERN1 expression led to increased XBP1s mRNA and protein levels. Furthermore, ChIP-seq analysis revealed that XBP1s binds enhancers upon stress stimuli regulating genes involved in UPR processes, eIF2 signaling and protein ubiquitination. We further demonstrate genomic overlap of AR- and XBP1s-binding sites, suggesting genomic conversion of the two signaling cascades. Transcriptomic effects of XBP1 were further studied by knockdown experiments, which lead to decreased expression of androgen-responsive genes and UPR genes. These results suggest a two-step mechanism of gene regulation, which involves androgen-induced expression of ERN1, thereby enhancing XBP1 splicing and transcriptional activity. This signaling cascade may prepare the cells for the increased protein folding, mRNA decay and translation that accompanies AR-regulated tumor cell proliferation.

Supplementary Materials

    • Supplementary Figure 1: XBP1s expression in clinical datasets.
    • Supplementary Figure 2: R1881 induced XBP1 splicing in prostate cancer cells.
    • Supplementary Figure 3: XBP1s target genes and ChIP-seq replicates.
    • Supplementary Figure 4: Testing XBP1s antibody specificity.
    • Supplementary Figure 5: Validation of XBP1s ChIP-seq analyses.
    • Supplementary Figure 6: ReMap tool analyses show overlap between XBP1s binding sites and those of other transcription factors.
    • Supplementary Figure 7: XBP1s overexpression induces expression of its target genes, but no AR-responsive genes in multiple prostate cancer cell lines.
    • Supplementary Figure 8: Validation of RNA-seq analyses.
    • Supplementary Table 1: Primer sequences.
    • Supplementary Table 2: Illumina sequencing data for ChIP-seq, number of sequenced and aligned reads and number of peaks
    • Supplementary Table 3: Relation of XBP1 mRNA expression with clinical pathological parameters
    • Supplementary Table 4: Relation of XBP1s expression with clinical pathological parameters
    • Supplementary Table 5: DARANA study (NCT03297385) – patient characteristics (prior to treatment).

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
13
Received Date:
26 Nov 2019
Accepted Date:
05 Dec 2019
Print Publication Date:
01 Feb 2020
Online Publication Date:
Feb 2020
Keywords:
androgen receptor; XBP1 splicing; ChIP-seq; unfolded protein response

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