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Androgen-induced modulation of XBP1s 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121880 | GEO | 2019/12/18

REPOSITORIES: GEO

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Dual role of the unfolded protein response in the therapeutic effect of AZD1775 on TP53 mutant high grade serous ovarian cancer

Project description:we demonstrate that the WEE1 inhibitor AZD1775 triggers endoplasmic reticulum (ER) stress and activates the PERK and IRE1α branches of the unfolded protein response (UPR) in TP53 mutant HGSOC cells. Upon AZD1775 treatment, PERK facilitates apoptotic signaling in these cells via activating CHOP, whereas IRE1α-induced spliced XBP1 (XBP1s) confers survival in response to WEE1 inhibition. Our data uncover an important dual role of UPR in TP53 mutant HGSOC cells in response to AZD1775, where additional inhibition of IRE1α-XBP1s signaling may offer synergistic efficacy.

2021-02-10 | GSE166417 | GEO

Profiling gene expression in 32Dcl3 cells following Xbp1 retrovirus vector transfection

Project description:The significant changes of hematopoietic cells induced by Xbp1S expression indicate that there is global alteration in gene expression. UPR induces transcription of Xbp1, and phosphorylation of the ER transmembrane kinase IRE1 initiates UPR-mediated mRNA splicing of Xbp1, resulting in the production of Xbp1S, an active form of a basic leucine zipper transcription factor. In the present study, Xbp1S retrovirus vector infected 32cl3 cells show cell cycle arrest and myeloid differentiation. Xbp1S may modulate important genes of differentiation and the cell cycle. RNA samples extracted from 32Dcl3 cells with pMIG (empty vector), pMY-Xbp1U (unspliced form) and pMY-Xbp1S (spliced form) retroviral vector transfected cells were subjected to expression profiling using the Affymetrix GeneChip microarray system.

2010-10-01 | E-GEOD-17023 | biostudies-arrayexpress

Profiling gene expression in 32Dcl3 cells following Xbp1 retrovirus vector transfection

2010-10-01 | GSE17023 | GEO

A CRISPR/Cas9-mediated screen identifies regulators of early plasma cell differentiation

Project description:The differentiation of B cells into antibody-secreting cells depends on cell division-coupled, epigenetic and other cellular processes that are incompletely understood. We have developed a CRISPR/Cas9-based screen that models an early stage of T cell-dependent plasma cell differentiation and measures B cell survival or proliferation versus the formation of CD138+ plasmablasts. Here, we refined and extended this screen to more than 500 candidate genes that are highly expressed in plasma cells. Among known genes whose deletion preferentially affected plasmablast formation were the transcriptional regulators Prdm1, Irf4 and Pou2af1, and the Ern1 gene encoding the ER stress sensor IRE1a. Moreover, we newly identified several genes involved in NF-kB or p38 signaling (Pim2, Nfkbia, Mapk14), vesicle trafficking (Arf4, Preb) and epigenetic regulators that form part of the NuRD complexes (Hdac1, Mta2, Mbd2). Defective plasmablast formation caused by Ern1 deletion could not be rescued by spliced XBP1 (XBP1s), a transcription factor dependent on and downstream of IRE1a, suggesting that in early plasma cell differentiation IRE1a acts independently of XBP1s. The deletion of ARF4, a small GTPase required for ER-to-Golgi transport, impaired plasmablast formation by blocking antibody secretion. Plasmablast formation after Hdac1 deletion was consistently reduced by about 50%, while deletion of the closely related Hdac2 gene had no effect. Hdac1 knock-out led to strongly perturbed protein expression of antagonistic transcription factors that specify plasma cell versus B cell identity (by decreasing IRF4 and BLIMP1 and increasing BACH2 and PAX5). Taken together, our results highlight specific and non-redundant roles for Ern1, Arf4 and Hdac1 in the early steps of plasma cell differentiation.

2022-12-22 | PXD038201 | Pride

Genome-wide mRNA profiling identifies X-box-binding protein 1 (XBP1) as an IRE1 and PUMA repressor

Project description:Previous studies suggested that XBP1s is important in deciding cell fate during the UPR, however, the mechanistic details of how it modulates this transition are limited. To search for XBP1s transcriptional targets, we utilized an XBP1s-inducible human cell line to limit XBP1 expression in a controlled manner.

2021-10-12 | GSE160416 | GEO

XBP1s cutnrun

Project description:The unfolded protein response (UPR) has emerged as important signaling pathway mediating anti-viral defenses to Respiratory Syncytial Virus (RSV) infection. In this study, we examine how Inositol Requiring Enzyme (IREa X-Box Binding Protein spliced (XBP1s) arm of the Unfolded Protein Response (UPR) pathway controls the innate response integrating RNA-seq and Cleavage Under Targets and Release Using Nuclease (CUT&RUN) analyses. XBP1s binds to ~4.2 K high-confidence genomic binding sites. Surprisingly these map to only a small subset of IL10/cytokine genes. We further find that that RSV infection enhances XBP1s occupancy on 786 genomic sites enriched in AP1/Fra-1, RELA and SP1 binding sites controlling a core subset of cytokine regulatory factors genes including IFN response factor 1 (IRF1), CSF2, NFKB1A and DUSP10. Selective IRF1 knockdown experiments demonstrates its requirement in control of type I and -III IFNs and IFN-stimulated genes (ISGs) indicating these genes are indirectly regulated through IRF1 transactivation. We conclude that RSV modulates the XBP1 binding complex to the IRF1 epromoter, providing novel insight into how the IRE1-XBP1s pathway potentiates airway mucosal anti-viral responses.

2023-04-30 | GSE228328 | GEO

The IRE1Î±-XBP1 Pathway of the Unfolded Protein Response is Required for Adipogenesis

Project description:Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARÎ³ and C/EBPÎ±. Here we demonstrate that the IRE1Î±-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryonic fibroblasts and 3T3-L1 cells with XBP1 or IRE1Î± knockdown exhibit profound defects in adipogenesis. Intriguingly, C/EBPÎ², a key early adipogenic factor, induces Xbp1 expression by directly binding to its proximal promoter region. Subsequently, XBP1 binds to the promoter of Cebpa and activates its gene expression. The posttranscriptional splicing of Xbp1 mRNA by IRE1Î± is required as only the spliced form of XBP1 (XBP1s) rescues the adipogenic defect exhibited by XBP1-deficient cells. Taken together, our data show that the IRE1Î±-XBP1 pathway plays a key role in adipocyte differentiation by acting as a critical regulator of the morphological and functional transformations during adipogenesis. The Xbp1 deficient MEFs are subjected to adipogenesis using standard drug induction. The cells are collected at day 0 and day 3. Total RNA are extracted from the cells and used for one channel microarray analysis. Expression levels on day 3 are compared to that on day 0.

2010-06-19 | E-GEOD-15771 | biostudies-arrayexpress

Transcriptional regulation of hematopoietic stem cell progenitors and acute myeloid leukemia by the IRE1a-XBP1 pathway [overexpression]

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2023-12-30 | GSE163137 | GEO

Effect of neuron-specific spliced XBP1 (XBP1s) overexpression on gene expression in the mouse brain

Project description:One major component of cellular proteome resides in the endoplasmic reticulum (ER), the key organelle for protein biogenesis in the secretory pathway. Disruption of ER proteostasis leads to ER stress, which subsequently activates multiple adaptive stress response pathways, collectedly termed as the unfolded protein response (UPR). One UPR branch is mediated by IRE1(inositol-requiring enzyme 1). Activation of the IRE1 UPR branch generates a potent transcriptional factor: spliced X-box–binding protein-1 (XBP1s). Since activation of this UPR branch has been shown to be neuroprotective in brain ischemia/stroke, it is critical to identify the XBP1s-regulated genes in neurons in vivo and thus help determine the molecular mechanisms underlying the beneficial effects exerted by this UPR branch. In this study, we performed RNA-Seq analysis on the hippocampus from XBP1s conditional transgenic mice.

2022-10-22 | GSE160263 | GEO

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

Project description:Alteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger effects in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson´s and Huntington´s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

2022-09-13 | PXD022554 | Pride

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