G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA576506 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Speckle-type POZ protein (SPOP), an E3 ubiquitin ligase, acts as a tumor suppressor. We identified G3BP1 as non-substrate interactor of SPOP. G3BP1 is a well-known oncogene in many cancer types, but its role in prostate cancer (PCa) remains largely elusive. We showed that G3BP1 functions as an upstream regulator and potent endogenous inhibitor of Cul3SPOP, suggesting a distinctive Cul3SPOP inactivation independent of SPOP mutations. Transcriptomic analysis together with functional studies revealed that the G3BP1-SPOP ubiquitin signaling axis is involved in PCa progression through activating AR signaling. Further, AR upregulates G3BP1 to potentiate feed-forward amplification of signaling through G3BP1-SPOP axis. Overall, we show G3BP1high PCa tumors constitute a new subset where G3BP1 inhibits Cul3SPOP function to upregulate AR signaling, and promotes tumorigenesis.
2021-09-26 | GSE138612 | GEO
Project description:SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3SPOP, suggesting a distinctive mode of Cul3SPOP inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3SPOP, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1high PCa are more susceptible to AR-targeted therapy.
2021-11-25 | PXD029120 | Pride
Project description:SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3SPOP, suggesting a distinctive mode of Cul3SPOP inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3SPOP, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1high PCa are more susceptible to AR-targeted therapy.
| S-EPMC8602290 | biostudies-literature
Project description:Mitochondrial calcium signaling plays a critical role in mitochondrial homeostasis during non-alcoholic steatohepatitis (NASH) progression. Here, we report Ras‐GTPase activating protein SH3 domain‐binding protein 1 (G3BP1), a core protein of stress granule (SG), significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Hepatocyte-specific G3BP1 deficiency attenuates NASH in two dietary mouse models. SG and the mitochondrial import protein TOM70 collaboratively mediate the translocation of G3BP1 to the mitochondria. G3BP1 interacts and stabilizes mitochondrial calcium uptake 1 (MICU1) via inhibiting YME1L1-mediated degradation of MICU1, and also impedes MCU complex activity and assembly, leading to mitochondrial calcium overload. Moreover, metabolic stress suppresses TRIM25-mediated K63-ubiquitination of G3BP1 and subsequent SG disassembly. Pharmacological inhibition of G3BP1 impairs the G3BP1-MICU1 interaction and prevents mitochondrial homeostasis imbalance and NASH progression. Collectively, we uncover the significant role of mitochondrial G3BP1 in mitochondrial homeostasis and NASH progression, which provides a potential target for therapeutic interventions.
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Project description:We examine the role of G3bp1, a RNA binding protein and site specific endoribonuclease in gene expression in isolated neonatal cardiomyocytes. RNAseq data from cardiomyocytes were infected with adenoviruses expressing shRNA against G3bp1 (ad-siG3bp1) or Luciferase (ad-siLUC, control) showed significant decrease in transcript abudnnace of cardiac-enriched genes involved in Calcium handling, contraction, action potential and sacromere function. On the other hand increase was observed in genes that regulate Hippo, TNF and TGFb signaling. Knockdown of G3bp1 inhibited endothelin-1 induced cardiomyocyte hypertrophy.
2022-01-14 | GSE184441 | GEO
Project description:Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe the first mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia, and invasive poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor (AR) signaling, effectively uncoupling the normal negative feedback between these two pathways. Associated RNA-seq data deposited in GEO: GSE94839.
2017-03-20 | PXD005309 | Pride
Project description:Mitochondrial calcium signaling plays a critical role in mitochondrial homeostasis during non-alcoholic steatohepatitis (NASH) progression. Here, we report Ras‐GTPase activating protein SH3 domain‐binding protein 1 (G3BP1), a core protein of stress granule (SG), significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Hepatocyte-specific G3BP1 deficiency attenuates NASH in two dietary mouse models. SG and the mitochondrial import protein TOM70 collaboratively mediate the translocation of G3BP1 to the mitochondria. G3BP1 interacts and stabilizes mitochondrial calcium uptake 1 (MICU1) via inhibiting YME1L1-mediated degradation of MICU1, and also impedes MCU complex activity and assembly, leading to mitochondrial calcium overload. Moreover, metabolic stress suppresses TRIM25-mediated K63-ubiquitination of G3BP1 and subsequent SG disassembly. Pharmacological inhibition of G3BP1 impairs the G3BP1-MICU1 interaction and prevents mitochondrial homeostasis imbalance and NASH progression. Collectively, we uncover the significant role of mitochondrial G3BP1 in mitochondrial homeostasis and NASH progression, which provides a potential target for therapeutic interventions.
2023-12-13 | GSE249869 | GEO
Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.
2023-10-11 | MTBLS8034 | MetaboLights