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

Suzan Stelloo, Simon Linder, Ekaterina Nevedomskaya, Eider Valle-Encinas, Iris de Rink, Lodewyk F.A. Wessels, Henk van der Poel, Andries M. Bergman (Corresponding author), Wilbert Zwart (Corresponding author)

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)67-79
Aantal pagina's13
TijdschriftEndocrine-related cancer
Volume27
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - 1 feb 2020

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  • Citeer dit

    Stelloo, S., Linder, S., Nevedomskaya, E., Valle-Encinas, E., de Rink, I., Wessels, L. F. A., van der Poel, H., Bergman, A. M., & Zwart, W. (2020). Androgen modulation of XBP1 is functionally driving part of the AR transcriptional program. Endocrine-related cancer, 27(2), 67-79. https://doi.org/10.1530/ERC-19-0181