BUB1 drives the occurrence and development of bladder cancer by mediating the STAT3 signaling pathway

Abstract

Background The incidence of bladder urothelial carcinoma (UC), a common malignancy of the urinary tract, is approximately three times higher in men than in women. High expression of the mitotic kinase BUB1 is associated with the occurrence and development of several cancers, although the relationship between BUB1 and bladder tumorigenesis remains unclear. Methods Using a microarray approach, we found increased BUB1 expression in human BCa. The association between BUB1 and STAT3 phosphorylation was determined through molecular and cell biological methods. We evaluated the impact of pharmacologic inhibition of BUB1 kinase activity on proliferation and BCa progression in vitro and in vivo. Results In this study, we found that BUB1 expression was increased in human bladder cancer (BCa). We further identified through a series of molecular and cell biological approaches that BUB1 interacted directly with STAT3 and mediated the phosphorylation of STAT3 at Ser727. In addition, the findings that pharmacologic inhibition of BUB1 kinase activity significantly suppressed BCa cell proliferation and the progression of bladder cancer in vitro and in vivo were further verified. Finally, we found that the BUB1/STAT3 complex promoted the transcription of STAT3 target genes and that depletion of BUB1 and mutation of the BUB1 kinase domain abrogated this transcriptional activity, further highlighting the critical role of kinase activity in the activation of STAT3 target genes. A pharmacological inhibitor of BUB1 (2OH-BNPP1) was able to significantly inhibit the growth of BCa cell xenografts. Conclusion This study showed that the BUB1 kinase drives the progression and proliferation of BCa by regulating the transcriptional activation of STAT3 signaling and may be an attractive candidate for therapeutic targeting in BCa.

Comprehensive analysis of BUBs gene family in lung adenocarcinoma with immunological analysis

“…Additionally, BUB1/3 are simultaneously overexpressed in gastric tumors and exhibit a significant correlation with Ki-67 expression [ 13 ]. BUB1 was found to modulate the G2/M transition to promote the proliferation of non-muscle-invasive bladder cancer cells [ 14 ] and drove the progression and proliferation of bladder cancer by regulating the transcriptional activation of STAT3 signaling [ 15 ]. Moreover, BUB1 promotes the proliferation and vertical migration ability of liver cancer cells by activating phosphorylation of SMAD2 [ 16 , 17 ].…”

Lipedema: Insights into Morphology, Pathophysiology, and Challenges

“…Among the genes related to cell mitotic pathways regulating the spindle-assembly checkpoint, whose expressions were altered in lipedema ADSCs, BUB1 was found to be of particular interest. As a mitotic checkpoint serine/threonine kinase, BUB1 overexpression has been associated with increased cellular proliferation and has been implicated in several cancers [ 139 , 140 , 141 ]. With regard to lipedema, it was postulated that, by increasing the phosphorylation of histone H2A, BUB1 interrupts the checkpoint between the G1 to the S phase of the cell cycle, leading to an increased number of cells in the S/synthesis phase, followed by decreased expression of PPARG, thereby causing a delay in the process of differentiation [ 142 ].…”

ZWINT is a cancer prognosis and immune infiltration-related biomarker from pan-cancer analysis

“…BUB1 promotes bladder carcinogenesis by mediating the STAT3 signaling pathway. NUF2 possesses high accuracy in distinguishing between highrisk and low-risk KIRC patients (Jiang et al, 2021). The gene set enrichment analysis and protein-protein interaction analysis of ZWINT revealed that ZWINT was signi cantly associated with mitotic cell cycle, regulation of cell cycle process, regulation of mitotic nuclear division, spindle elongation and chromosome localization.…”