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Androgen modulation of XBP1 is functionally driving part of the AR transcriptional program.
Stelloo, Suzan; Linder, Simon; Nevedomskaya, Ekaterina; Valle-Encinas, Eider; de Rink, Iris; Wessels, Lodewyk F A; van der Poel, Henk; Bergman, Andries M; Zwart, Wilbert.
Afiliação
  • Stelloo S; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Linder S; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Nevedomskaya E; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Valle-Encinas E; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • de Rink I; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Wessels LFA; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • van der Poel H; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • Bergman AM; Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands.
  • Zwart W; Division of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Endocr Relat Cancer ; 27(2): 67-79, 2020 Feb.
Article em En | MEDLINE | ID: mdl-31804970
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Receptores Androgênicos / Regulação Neoplásica da Expressão Gênica / Proteínas Serina-Treonina Quinases / Endorribonucleases / Resposta a Proteínas não Dobradas / Proteína 1 de Ligação a X-Box / Androgênios Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Próstata / Receptores Androgênicos / Regulação Neoplásica da Expressão Gênica / Proteínas Serina-Treonina Quinases / Endorribonucleases / Resposta a Proteínas não Dobradas / Proteína 1 de Ligação a X-Box / Androgênios Idioma: En Ano de publicação: 2020 Tipo de documento: Article