IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling

Sheng, Xia; Nenseth, Hatice Zeynep; Qu, Su; Kuzu, Omer F.; Frahnow, Turid; Simon, Lukas M.; Greene, Stephanie; Zeng, Qingping; Fazli, Ladan; Rennie, Paul S.; Mills, Ian G.; Danielsen, Håvard E.; Theis, Fabian J.; Patterson, John B.; Jin, Yang; Saatcioglu, Fahri

doi:10.1038/s41467-018-08152-3

Cited by 167 publications

(161 citation statements)

References 52 publications

Supporting

Mentioning

157

Contrasting

Order By: Relevance

“…[4], PKM2 [5], REST4 [6], XBP1s [7], In1-Ghrelin [8] among others, has also been found to be associated to PCa development and progression. In this sense, it is reasonable to think that a dysregulation of the cellular machinery involved in the control of splicing process would be responsible for the broad alteration of oncogenic SVs observed in PCa.…”

Section: Discussionmentioning

confidence: 99%

“…increased risk of biochemical relapse and inferior overall survival outcomes). In addition, a number of cancer-specific SVs has been identified in PCa, including SST 5 TMD4 [4], PKM2 [5], REST4 [6], XBP1s [7], In1-Ghrelin [8] etc., which also play an oncogenic role in this tumor pathology. In fact, it has been proposed that the "splicing signature" represents a more accurate parameter to stratify patients than the "transcriptome signature", which is typically analysed by conventional microarray analyses [9].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

et al. 2020

View full text Add to dashboard Cite

Background: Dysregulation of splicing variants (SVs) expression has recently emerged as a novel cancer hallmark. Although the generation of aberrant SVs (e.g. AR-v7/sst5TMD4/etc.) is associated to prostate-cancer (PCa) aggressiveness and/or castration-resistant PCa (CRPC) development, whether the molecular reason behind such phenomena might be linked to a dysregulation of the cellular machinery responsible for the splicing process [spliceosome-components (SCs) and splicing-factors (SFs)] has not been yet explored. Methods: Expression levels of 43 key SCs and SFs were measured in two cohorts of PCa-samples: 1) Clinicallylocalized formalin-fixed paraffin-embedded PCa-samples (n = 84), and 2) highly-aggressive freshly-obtained PCa-samples (n = 42). Findings: A profound dysregulation in the expression of multiple components of the splicing machinery (i.e. 7 SCs/19 SFs) were found in PCa compared to their non-tumor adjacent-regions. Notably, overexpression of SNRNP200, SRSF3 and SRRM1 (mRNA and/or protein) were associated with relevant clinical (e.g. Gleason score, T-Stage, metastasis, biochemical recurrence, etc.) and molecular (e.g. AR-v7 expression) parameters of aggressiveness in PCa-samples. Functional (cell-proliferation/migration) and mechanistic [gene-expression (qPCR) and protein-levels (western-blot)] assays were performed in normal prostate cells (PNT2) and PCa-cells (LNCaP/22Rv1/PC-3/ DU145 cell-lines) in response to SNRNP200, SRSF3 and/or SRRM1 silencing (using specific siRNAs) revealed an overall decrease in proliferation/migration-rate in PCa-cells through the modulation of key oncogenic SVs expression levels (e.g. AR-v7/PKM2/XBP1s) and alteration of oncogenic signaling pathways (e.g. p-AKT/p-JNK). Interpretation: These results demonstrate that the spliceosome is drastically altered in PCa wherein SNRNP200, SRSF3 and SRRM1 could represent attractive novel diagnostic/prognostic and therapeutic targets for PCa and CRPC.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Notably, one of the identified miR-34c-5p targets was the receptor tyrosine kinase activated by hepatocyte growth factor that is crucial for metastatic progression (63). Interestingly, other studies correlated increased XBP1s levels with poor cancer survival prognosis (64)(65)(66)(67). These studies proposed that the IRE1-a-XBP1s pathway promotes prostate cancer by activating Myc proto-oncogene protein signaling (67), promotes colorectal cancer by suppressing transcriptional activity of tumor suppressor tumor protein P73 (a member of p53 family), and promotes triple-negative breast cancer by controlling the hypoxia-inducible factor 1 pathway (66).…”

Section: Discussionmentioning

confidence: 99%

miR‐34c‐5p modulates X‐box–binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response

Bartoszewska¹,

Cabaj

Dąbrowski

et al. 2019

FASEB j.

View full text Add to dashboard Cite

During endoplasmic reticulum (ER) stress conditions, an adaptive signaling network termed the unfolded protein response (UPR) is activated. The UPR's function is to increase ER protein‐folding capacity in order to attenuate ER stress, restore ER homeostasis, and, most importantly, promote cell survival. X‐box–binding protein 1 (XBP1) is one component of the UPR and is a proadaptive transcription factor that is subject to transcriptional, post‐transcriptional, and post‐translational control. In the present study, we identified a post‐transcriptional mechanism mediated by miR‐34c‐5p that governs the expression of both the spliced (active) and unspliced (latent) forms of XBP1 mRNAs. We showed that miR‐34c‐5p directly attenuates spliced XBP1 (XBP1s) mRNA levels during ER stress and thus regulates the proadaptive component of the UPR that is mediated by XBP1s without interfering with the induction of apoptotic responses.—Bartoszewska, S., Cabaj, A., Dabrowski, M., Collawn, J. F., Bartoszewski, R. miR‐34c‐5p modulates X‐box‐binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response. FASEB J. 33, 11541–11554 (2019). http://www.fasebj.org

show abstract

“…TNBC also coopts the UPR, as shown by seminal published work implicating XBP1s in conjunction with HIF1 in driving TNBC tumor angiogenesis and progression under hypoxia (26). More recent studies also have linked the IRE1-XBP1s axis to the oncogenic transcription factor MYC-a potent driver of proliferation and protein synthesis (27)-in TNBC (28), prostate cancer (29), and B-cell lymphoma (30). Pharmacologic inhibition of IRE1 via its RNase domain markedly augmented the effectiveness of taxane chemotherapy in cellline-based or patient-derived xenograft TNBC models (28,31).…”

Section: Introductionmentioning

confidence: 98%

IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

Harnoss¹,

Thomas²,

Reichelt³

et al. 2020

Cancer Research

View full text Add to dashboard Cite

Cancer cells exploit the unfolded protein response (UPR) to mitigate endoplasmic reticulum (ER) stress caused by cellular oncogene activation and a hostile tumor microenvironment (TME). The key UPR sensor IRE1α resides in the ER and deploys a cytoplasmic kinase-endoribonuclease module to activate the transcription factor XBP1s, which facilitates ER-mediated protein folding. Studies of triple-negative breast cancer (TNBC)-a highly aggressive malignancy with a dismal post-treatment prognosisimplicate XBP1s in promoting tumor vascularization and progression. However, it remains unknown whether IRE1α adapts the ER in TNBC cells and modulates their TME, and whether IRE1α inhibition can enhance anti-angiogenic therapy-previously found to be ineffective in TNBC patients. To gauge IRE1α function, we defined an XBP1s-dependent gene signature, which revealed significant IRE1α pathway activation in multiple solid cancers, including TNBC. IRE1α knockout in TNBC cells markedly reversed substantial ultrastructural expansion of the ER within these cells upon growth in vivo. IRE1α disruption also led to significant remodeling of the cellular TME, increasing pericyte numbers while decreasing cancer-associated fibroblasts and myeloid-derived suppressor cells. Pharmacological IRE1α kinase inhibition strongly attenuated growth of cell-line-based and patient-derived TNBC xenografts in mice and synergized with anti-VEGF-A treatment to cause tumor stasis or regression. Thus, TNBC cells critically rely on IRE1α to adapt their ER to in vivo stress and to adjust the TME to facilitate malignant growth. TNBC reliance on IRE1α is an important vulnerability that can be uniquely exploited in combination with anti-angiogenic therapy as a promising new biologic approach to combat this lethal disease. Statement of significance Pharmacologic IRE1α kinase inhibition reverses ultrastructural distension of the ER, normalizes the tumor vasculature, and remodels the cellular tumor microenvironment, attenuating TNBC growth in mice. Research.

show abstract

IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling

Cited by 167 publications

References 52 publications

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

miR‐34c‐5p modulates X‐box–binding protein 1 (XBP1) expression during the adaptive phase of the unfolded protein response

IRE1α Disruption in Triple-Negative Breast Cancer Cooperates with Antiangiogenic Therapy by Reversing ER Stress Adaptation and Remodeling the Tumor Microenvironment

Contact Info

Product

Resources

About