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A nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth

ABSTRACT: Endoplasmic-reticulum resident inositol-requiring enzyme 1a (IRE1) supports protein homeostasis via its cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and of regulated RNA decay. We discovered that some cancer cells surprisingly require IRE1 but not its enzymatic activity. IRE1 knockdown but not enzymatic IRE1 inhibition or XBP1 disruption attenuated cell cycle progression and tumor growth. IRE1 silencing led to activation of TP53 and CDKN1A/p21 in conjunction with increased DNA damage and chromosome instability, while decreasing heterochromatin as well as DNA and histone H3K9me3 methylation. Immunoelectron microscopy detected endogenous IRE1 at the nuclear envelope. Thus, cancer cells co-opt IRE1 either enzymatically or nonenzymatically, which has significant implications for IRE1’s biological role and therapeutic targeting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285981 | GEO | 2025/01/07

REPOSITORIES: GEO

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leA nonenzymatic dependency on inositol-requiring enzyme 1 controls cancer cell cycle progression and tumor growth

Project description:Endoplasmic-reticulum resident inositol-requiring enzyme 1alpha(IRE1) supports protein homeostasis via a cytoplasmic kinase-RNase module. Known cancer dependency on IRE1 entails its enzymatic activation of the transcription factor XBP1s and of RNA decay. We discovered that some cancer cells require IRE1 but not its enzymatic activity. IRE1 knockdown, but not enzymatic inhibition or XBP1 disruption, increased DNA damage and chromosome instability while engaging the TP53 pathway and cyclin-dependent kinase inhibitors, and attenuated cell cycle progression. IRE1 depletion downregulated factors involved in chromosome replication and segregation and in chromatin remodeling. Immunoelectron microscopy indicated that endogenous IRE1 can localize to the nuclear envelope. Thus, cancer cells can require IRE1 either enzymatically or nonenzymatically, with significant implications for IRE1's biological role and therapeutic targeting.

2024-01-22 | MSV000093902 | MassIVE

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.

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Pharmacologic IRE1/XBP1s Activation Confers Targeted ER Proteostasis Reprogramming

Project description:Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly-selective IRE1 activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.

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Bulk RNAseq of control, XBP1-deficient or XBP1/IRE1-deficient cDC1s from subcutaneous B16- melanoma bearing mice

Project description:The unfolded protein response (UPR) sensor IRE1 and its target, the transcription factor XBP1s critically regulate the function of dendritic cell (DC) subtypes. However, the contribution of the IRE1/XBP1s axis in DCs to the antitumor immunity is not entirely understood. Here, using reporter mice we found that DCs, in particular type 1 conventional DCs (cDC1s), are major targets of IRE1 RNase activity in melanoma tumors. Deletion of XBP1s in CD11c+ cells resulted in augmented tumor growth, impaired effector T cell responses and decreased accumulation of TCF-1+CD8+ T cells with a precursor exhausted profile. Transcriptomic studies revealed that XBP1 deletion in tumor cDC1s induced regulated IRE1 dependent decay (RIDD) of mRNAs, which accounted for the dysregulated T cell immunity in melanoma. Thus, a strict regulatory circuit involving IRE1 RNase and XBP1s in DCs ensures optimal antitumor T cell immunity in melanoma models.

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2021-10-29 | PXD026653 | Pride

The UPR Transducer IRE1 Promotes Breast Cancer Malignancy by Degrading Tumor Suppressor microRNAs

Project description:To understand the mechanistic basis by which inositol-requiring enzyme 1 (IRE1) is involved in luminal breast cancer malignancy, we analyzed the transcriptomic signature that IRE1 regulates in breast cancer. We suppressed the activity of IRE1 RNase in luminal breast cancer SUM52 line by adenoviral-based over-expression of the IRE1 dominant-negative K599A or K907A, and then performed RNA-sequencing (RNA-seq) analysis with IRE1 dominant-negative and control SUM52 cells. Through the RNA-seq analysis, we identified 98 genes that were commonly upregulated (65 genes) or downregulated (33 genes) in K599A-expressing SUM52 (SUM52-K599A) or K907A-expressing SUM52 (SUM52-K907A) cells.

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2018-08-15 | GSE99766 | GEO

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

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.

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