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Target BUB1 kinase as a therapeutic strategy for inhibiting STAT3 signal pathway in Bladder cancer

ABSTRACT: Target BUB1 kinase as a therapeutic strategy for inhibiting STAT3 signal pathway in Bladder cancer

PROVIDER: PRJNA534083 | ENA |

REPOSITORIES: ENA

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			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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Target BUB1 kinase as a therapeutic strategy for inhibiting STAT3 signal pathway in Bladder cancer

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

TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3

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

TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3

Project description:TRIM59 promotes gliomagenesis by inhibiting TC45 dephosphorylation of STAT3

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TIC regulates hypocotyl growth in Arabidopsis by inhibiting PHYA signal

Project description:TIC regulates hypocotyl growth in Arabidopsis by inhibiting PHYA signal

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Gene expression profiling of C/EBPM-NM-2- and STAT3-deficient human endometrial stromal cells (HESC)

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

Micheliolide exerts effects in MPNs by inhibiting STAT3/5 activation via covalently binding to STAT3/5 proteins

Project description:Micheliolide exerts effects in MPNs by inhibiting STAT3/5 activation via covalently binding to STAT3/5 proteins

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Study target genes of STAT3

Project description:This study is to identify downstream genes regulated by STAT3 in response cytosolic acidification. Dysregulated intracellular pH is emerging as a hallmark of cancer. In spite of their acidic environment, cancer cells maintain alkaline intracellular pH (≥7.4) that promotes cancer progression by inhibiting apoptosis and increasing glycolysis, cell growth, migration and invasion. Here, we identify signal transducer and activator of transcription 3 (STAT3) as a key player in the maintenance of alkaline cytosolic pH. STAT3 associates with the vacuolar H+-ATPase on lysosomal membranes in a coiled coil domain-dependent manner and increases its activity in living cells and in vitro. Accordingly, STAT3 depletion disrupts intracellular proton equilibrium by decreasing and increasing cytosolic and lysosomal pH, respectively. This dysregulation can be reverted by reconstitution with wild type STAT3 as well as STAT3 mutants unable to activate target genes (Tyr-705-Phe and DNA binding mutant) or to regulate mitochondrial respiration (Ser-727-Ala). Upon cytosolic acidification, phospho-Tyr-705-STAT3 is rapidly dephosphorylated, transcriptionally inactivated and further recruited to lysosomal membranes to reestablish intracellular proton equilibrium and to enhance cell survival. These data reveal STAT3 as a regulator of intracellular pH, and vice versa intracellular pH as a regulator of STAT3 localization and activity.

2018-01-03 | GSE108495 | GEO

The STAT3 induced ITGB4 overexpression represses p53 to reduce the sensitivity of bladder cancer to cisplatin

Project description:Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer, but the development of cisplatin-resistance limits its anti-tumor effects. Previous studies have shown that cisplatin resistance in bladder cancer may be related to a variety of factors, such as changes in drug transport and metabolism, enhancement of DNA repair mechanisms, changes in cell cycle regulation, inhibition of apoptosis, and epigenetic modification. While, the mechanism of cisplatin resistance is still elusive.In this study, we first found that upregulated ITGB4 is correlated with poor prognosis after chemotherapy in bladder cancer. Next, we demonstrated ITGB4 plays a key role in regulating the sensitivity of bladder cancer to cisplatin therapy. Then, we found that ITGB4 reduced the sensitivity of bladder cancer to cisplatin by inhibiting p53-S15 site phosphorylation and promoting MDM2 binding to p53 to reduce p53 expression. In addition, we demonstrated that ITGB4 regulates the antitumor effects of MDM2 inhibitors combined with cisplatin therapy. Further, we found that ITGB4 was elevated in bladder cancer cisplatin-resistant cells, and the increase in ITGB4 was mediated by STAT3.The combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin in bladder cancer.In summary, we identified ITGB4 as a key molecule affecting cisplatin sensitivity in bladder cancer, and proposed a strategy of combining drugs with STAT3 inhibitors to increase cisplatin sensitivity in bladder cancer.

2024-06-07 | GSE268855 | GEO

Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal

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The Stat3 target Mettl8 regulates mouse ESCs differentiation via inhibiting JNK pathway

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