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

Abstract

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.

Integrated Analysis of Microbiome and Transcriptome Data Reveals the Interplay Between Commensal Bacteria and Fibrin Degradation in Endometrial Cancer

“…CPB2 is involved in the clotting-fibrinolytic pathway, and abnormal expression of this protein has been linked to thromboembolism and cancer ( Lip et al., 2002 ). XBP1 is a key transcription factor of the cellular secretory system, and it is often overexpressed in cancers, such as oral squamous cell carcinoma and hepatocellular carcinoma, and correlates with the clinical outcome ( Stelloo et al., 2020 ). Multiplex immunofluorescence confirmed that PRSS33, CPB2 and XBP1 proteins were significantly highly expressed in the endometrial tumor tissues of patients with elevated DD and FDPs ( Figure 4G ), suggesting that Prevotella could partially promote DD and FDPs by influencing host gene expression.…”

ATF6α promotes prostate cancer progression by enhancing PLA2G4A‐mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis

“…Furthermore, the UPR is sensitive to androgen and favors adaptive responses to promote the survival of PCa cells not only by activating IRE1a signaling but also by inhibiting the PERK‐eIF2a axis 27,28 . Further study illustrated that AR signaling and XBP1s coordinate prime proliferating prostate tumor cells for increased protein folding, mRNA decay, and protein translation 29 . These facts suggest that selectively manipulating UPR branches may be a therapeutic approach in PCa.…”

“… 27 , 28 Further study illustrated that AR signaling and XBP1s coordinate prime proliferating prostate tumor cells for increased protein folding, mRNA decay, and protein translation. 29 These facts suggest that selectively manipulating UPR branches may be a therapeutic approach in PCa. ATF6α is a member of the ATF/cAMP response element‐binding protein basic‐leucine zipper family of DNA‐binding proteins.…”

The Interplay between Finasteride-Induced Androgen Imbalance, Endoplasmic Reticulum Stress, Oxidative Stress, and Liver Disorders in Paternal and Filial Generation

“…Additionally, both pathways have some crosstalk, based on the IRE1α signaling branch [ 47 ]. It was also demonstrated that both UPR and ERAD are regulated by androgens [ 48 , 49 ]. In light of these reports, we want to theoretically consider that Fin administration and the associated androgen imbalance can affect the functions of the liver and hepatic ERet.…”