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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130145 | GEO | 2021/12/08

REPOSITORIES: GEO

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Project description:Dendritic cells (DC) play a vital role in the induction of activation or tolerance of immune response. STAT3 is a master transcriptional regulator of immune response in DCs by positively or negatively regulating DC function, but the mechanisms are unknown. STAT3 is post-translationally modified by acetylation or phosphorylation. While much is understood about transcriptional targets of phosphorylated STAT3, the gene targets and the functional impact of acetylated-STAT3 remain unclear. We aimed to answer the gene targets of acetylated-STAT3 and test the hypothesis that acetylation of STAT3 plays a key role in negative regulation of DCs. We performed genome-wide binding analysis of acetyl-STAT3 by ChIP-Seq coupled with gene expression microarrays. Acetylation of STAT3 induced by SAHA increased its capability to bind to target DNA sites in genome. Theses binding sites were mostly proximal but some were also distal up to over 100 kb from transcription start site. Gene expression array showed 1701 genes up-regulated and 1668 genes down-regulated. Proximal binding of acety-STAT3 showed more effective transcription function than distal binding. In top 500 binding peaks, the frequency of canonical motifs bound by acetyl-STAT3 were significantly higher than that for noncanonical motifs (p<0.00001). Functional analysis revealed that acetyl-STAT3 regulates target genes by upregulating genes that are primarily involved in negative regulation of cytokine production and IL-10 signaling, or downregulating genes that are primarily involved in immune effector process and antigen processing/presentation. Upregulation of IL-10Ra by acetyl-STAT3 contributes to the enhanced sensitivity of IL-10 signaling and negative regulation of DC function. Bone marrow derived dendritic cells were treated with SAHA (500 nm) or diluent for 12 hours. ChIP was performed using antibodies against STAT3, H3K4me3 and matched IgG control. DNA binding profiles were generated by deep sequencing using Illumina HiSeq 2000.

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

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