Target BUB1 kinase as a therapeutic strategy for inhibiting STAT3 signal pathway in Bladder cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA534083 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8938070_1.fastq.gz | Fastqsanger.gz | |||
| SRR8938070_2.fastq.gz | Fastqsanger.gz | |||
| SRR8938071_1.fastq.gz | Fastqsanger.gz | |||
| SRR8938071_2.fastq.gz | Fastqsanger.gz | |||
| SRR8938072_1.fastq.gz | Fastqsanger.gz |
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Project description:The incidence for bladder urothelial carcinoma (UC), a common malignancy of the urinary tract, is about three times higher in men than in women. High expression of the mitotic kinase BUB1 is associated with a subset of human cancers, but how BUB1 drive Bladder tumorigenesis mechanism was unknown. Using a microarray approach, we identified BUB1 higher expression in BC. Moreover we found BUB1, a member of the kinase family as a STAT3 interactor and phosphorylated STAT3 at Ser727 in cell of bladder cancer. In vitro binding and kinase assays showed that BUB1 directly band STAT3 and phosphorylated STAT3. Furthermore, the BUB1/STAT3 complex promoted STAT3 target gene transcription. Depletion of BUB1 and expression of BUB1 kinase mutants abrogated target gene transcription, highlighting the essential function of the kinase activity in STAT3 target gene activation. Pharmacological inhibitors of BUB1 (2OH-BNPP1) was able to inhibit the growth of Bladder cancer cell xenograft. This kinase may present an attractive candidate for drug targeting in Bladder cancer.
2021-12-08 | GSE130145 | GEO
Project description:Kinetochore localized Mad1 is essential for generating a “wait anaphase” signal during mitosis hereby ensuring accurate chromosome segregation. Inconsistent models for the function and quantitative contribution of the two mammalian Mad1 kinetochore receptors: Bub1 and the Rod-Zwilch-ZW10 (RZZ) complex exist. By combining genome editing and RNAi we achieve penetrant removal of Bub1 and Rod in human cells, which reveals that efficient checkpoint signaling depends on the integrated activities of these proteins. Rod removal reduces the proximity of Bub1 and Mad1 and we can bypass the requirement for Rod by tethering Mad1 to kinetochores or increasing the strength of the Bub1-Mad1 interaction. We find that Bub1 has checkpoint functions independent of Mad1 localization that are supported by low levels of Bub1 suggesting a catalytic function. In conclusion, our results support an integrated model for the Mad1 receptors in which the primary role of RZZ is to localize Mad1 at kinetochores to generate the Mad1-Bub1 complex.
2019-02-19 | PXD012235 | Pride
Project description:Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by synovitis and, bone and cartilage destruction. Although disease-modifying anti-rheumatic drugs (DMARDs) have dramatically improved clinical outcomes, these therapies are not universally effective in all patients due to the heterogeneity of RA pathogenesis. Therefore, there is still a need to elucidate molecular mechanisms underlying RA pathogenesis to identify novel therapeutic targets. In this study, we identified Budding uninhibited by benzimidazoles 1 (BUB1) was highly expressed in RA patients’ synovium and murine ankle tissue with arthritis. Since we revealed CD45+CD11b+ myeloid cells as Bub1 highly expressing population among synovial cells, myeloid cell-specific Bub1 conditional knockout (cKO) mice were generated. Obtained cKO mice showed no significant phenotypes in healthy conditions while they exhibited reduced bone mineral density under K/BxN serum-transfer arthritis. Moreover, histomorphometric analysis suggested that the reduced bone mass was caused by increased osteoclast differentiation and activation. RNA-seq and subsequent Gene set enrichment analysis (GSEA) demonstrated significantly enriched NF-κB pathway among up-regulated genes in RANKL-stimulated bone marrow macrophages obtained from Bub1 cKO, suggesting Bub1 KO macrophages are sensitive to inflammatory conditions. Indeed, osteoclastogenesis in Bub1 KO macrophages was enhanced by RANKL and TNFα treatment and localization of NF-κB component p65 was observed. Finally, osteoclastogenesis was increased by Bub1 inhibitor BAY1816032 treatment. These data suggested that BUB1 in myeloid cells plays a protective role against bone loss under inflammatory arthritis.
2024-04-12 | GSE241409 | GEO
Project description:Bub1 is required for the kinetochore/centromere localization of two essential mitotic kinases Plk1 and Aurora B. Surprisingly, stable depletion of Bub1 by ~95% in human cells marginally affects whole chromosome segregation fidelity. We show that CENP-U, which is recruited to kinetochores by the CENP-P and CENP-Q subunits of the CENP-O complex, is required to prevent chromosome mis-segregation in Bub1-depleted cells. Mechanistically, Bub1 and CENP-U redundantly recruit Plk1 to kinetochores to stabilize kinetochore-microtubule attachments, thereby ensuring accurate chromosome segregation. Furthermore, unlike its budding yeast homolog, the CENP-O complex does not regulate centromeric localization of Aurora B. Consistently, depletion of Bub1 or CENP-U sensitizes cells to the inhibition of Plk1 but not Aurora B kinase activity. Taken together, our findings provide mechanistic insight into the regulation of kinetochore function, which may have implications for targeted treatment of cancer cells with mutations perturbing kinetochore recruitment of Plk1 by Bub1 or the CENP-O complex.
2021-08-29 | GSE182827 | GEO
Project description:Our previous studies have shown that C/EBPM-NM-2 plays a critical role in human endometrial stromal decidualization. In order to identify the molecular pathways regulated by C/EBPM-NM-2 during decidualization, we performed gene expression profiling using RNA isolated from normal and C/EBPM-NM-2-deficient human endometrial stromal cells. The microarray results revealed that several key regulators of stromal differentiation, such as BMP2, Wnt4, IL-11RM-NM-1 and STAT3, operate downstream of C/EBPM-NM-2 during decidualization. Further studies revealed that STAT3 is a direct target of C/EBPM-NM-2 and plays an important role in cytokine signal during the decidualization process. Gene expression profiling, using STAT3-deficient HESCs, showed an extensive overlap of pathways downstream of STAT3 and C/EBPM-NM-2 during stromal cell differentiation. We employed a siRNA strategy to suppress C/EBPM-NM-2 or STAT3 mRNA expression in HESCs and then performed microarray analysis to identify its downstream target genes. Further, using a similar strategy, we focused on STAT3, a C/EBPM-NM-2 target gene, and identified the commone pathways downstream of both C/EBPM-NM-2 and STAT3.
2012-10-11 | E-GEOD-41473 | biostudies-arrayexpress
Project description:Malignant pleural mesothelioma (MPM) is a rare yet highly aggressive malignancy with a severe prognosis. Compounded by the lack of effective treatment modalities, MPM remains a formidable health challenge. Therefore, identification of actionable liabilities is critical for advancing precision medicine to combat this lethal disease. Here, we exploit an unbiased genome-wide CRISPR screen, integrating and cross-comparing three MPM cell lines with nonmalignant mesothelial cells, to selectively map the gene targets whose depletion indicates a common dependency in MPM cells. This systematic approach unveils a cohort of verifiable genes, among which BUB1, a mitotic checkpoint serine/threonine kinase, emerges as a high-confidence hit in cancer cells. Cellular and molecular studies demonstrate that genetic depletion or pharmacological inhibition of BUB1 profoundly impairs MPM cell survival and growth, while inducing G2/M cell cycle arrest, cellular senescence, and apoptosis, and attenuating functional hallmarks of aggressive cancer cells. Transcriptomic profiling of BUB1-depleted cells discloses differential gene expression signatures congruent with cell fate phenotypes, including the reprogramming of mitotic network genes. Mechanistically, BUB1 is indispensable for the proper localization of essential mitotic regulators MAD1, MAD2, and Shugoshin (SGO1), thereby ensuring the functionality of the spindle assembly checkpoint (SAC). Furthermore, BUB1 ablation leads to cytokinesis failure and multinucleation, a phenotype characterized by the downregulation of CDC20, Cyclin A, and Cyclin B, and a reciprocal upregulation of the cyclin-dependent kinase inhibitor p21. Clinically, MPM tumors exhibit elevated levels of BUB1, and high BUB1 expression is associated with shorter patient survival. Our novel findings accentuate comparative CRISPR screens as a powerful platform to explore tumor cell-selective gene essentiality and propose BUB1 kinase as a potential marker and druggable vulnerability with therapeutic implications for MPM.
2025-04-09 | GSE292620 | GEO
Project description:BUB1 is a nuclear serine/threonine protein kinase and a vital spindle assembly checkpoint (SAC) complex member responsible for proper chromosome segregation before mitosis. Here we report that BUB1 plays an unexpected cytoplasmic role in restraining DNA damage-induced accumulation of cytoplasmic dsRNA and ensuing immune response. We showed that tumors deficient in BUB1 were sensitive to radiotherapy in a CD8+T-cell-dependent manner. Furthermore, we discovered increased immune cell infiltration accompanied by elevated type I interferon production from irradiated BUB1-deficient cells, caused by enhanced cytoplasmic dsRNA accumulation and activation of the MDA5/MAVS/IRF7 dsRNA-sensing pathway. Mechanistically, we discovered that after exposure to ionizing radiation, BUB1 underwent a robust nucleus-to-cytoplasm migration, where it bound and phosphorylated the polyA-binding protein PABPC1, which was degraded together with its associated mRNAs stored in the stress granules, thereby preventing dsRNA accumulation and activation of the innate immune response. Our study, therefore, reveals a novel biological role for BUB1 in suppressing DNA-damage-induced cytoplasmic dsRNA accumulation/viral mimicry and provides a rationale for inhibiting BUB1 to enhance cytotoxic cancer therapy immunologically.
2025-10-18 | GSE246123 | GEO
Project description:BUB1 is a nuclear serine/threonine protein kinase and a vital spindle assembly checkpoint (SAC) complex member responsible for proper chromosome segregation before mitosis. Here we report that BUB1 plays an unexpected cytoplasmic role in restraining DNA damage-induced accumulation of cytoplasmic dsRNA and ensuing immune response. We showed that tumors deficient in BUB1 were sensitive to radiotherapy in a CD8+T-cell-dependent manner. Furthermore, we discovered increased immune cell infiltration accompanied by elevated type I interferon production from irradiated BUB1-deficient cells, caused by enhanced cytoplasmic dsRNA accumulation and activation of the MDA5/MAVS/IRF7 dsRNA-sensing pathway. Mechanistically, we discovered that after exposure to ionizing radiation, BUB1 underwent a robust nucleus-to-cytoplasm migration, where it bound and phosphorylated the polyA-binding protein PABPC1, which was degraded together with its associated mRNAs stored in the stress granules, thereby preventing dsRNA accumulation and activation of the innate immune response. Our study, therefore, reveals a novel biological role for BUB1 in suppressing DNA-damage-induced cytoplasmic dsRNA accumulation/viral mimicry and provides a rationale for inhibiting BUB1 to enhance cytotoxic cancer therapy immunologically.
2025-10-18 | GSE246124 | GEO
Project description:Although the oncogenic signalings driven by amplification and mutations of EGF receptor (EGFR) gene play a major role in glioblastoma pathogenesis, the responsible downstream mechanisms remain less clear. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59), acting as a new downstream effector of EGFR signaling, regulates STAT3 activation in glioblastoma. EGFR signaling leads to TRIM59 upregulation through SOX9 that results in enhancing TRIM59 interaction with STAT3 in nucleus, and inhibiting STAT3 association with TC45 (the nuclear form of T cell protein tyrosine phosphatase TC-PTP), thereby maintaining STAT3 phosphorylation and activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumorigenesis of GBM cells. Moreover, evaluation of GBM patient samples reveals an association among EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR-STAT3 signaling and a potential therapeutic target for GBM patients with EGFR activation.
2019-03-26 | GSE106557 | GEO
Project description:We identified a novel mechanism by which IL-6/STAT3 signaling up-regulates CD133 expression and promotes HCC progression. STAT3 activation upregulates the expression of CD133 during liver carcinogenesis. Targeting STAT3-mediated CD133 overexpression may represent a promising therapeutic strategy for HCC patients via eradicating the liver tumor microenviornment. To develop novel cancer therapeutic strategies by identification of signaling pathways or biomarkers and understanding their functions on cancer stem cell biology, we determined CD133 expression and STAT3 activation with tumor microenvironment in HCC patient tissues. The relation of STAT3 activation and CD133 expression was investigated by luciferase assay, shRNA knock-down, and chromatin immunoprecipitation assay in HCC cells, and in vivo xenograft model.
2014-08-08 | E-GEOD-60194 | biostudies-arrayexpress