Search

Background: Abnormal expression of splicing factor 3A subunit 3 (SF3A3), a component of the spliceosome, has been confirmed to be related to the occurrence and development of various cancers. However, the expression and function of SF3A3 in bladder cancer (BC) remains unclear., Methods: The SF3A3 mRNA and protein level were measured in clinical samples and cell lines by quantitative real-time PCR, Western blot and immunofluorescence staining. Evaluate the clinical correlation between SF3A3 expression and clinicopathological characteristics through statistical analysis in BC patients. The function of SF3A3 in BC cells was determined in vitro using MTT and colony analysis. Co-immunoprecipitation (CoIP) assay was used to detected E2F6 and KDM5C interaction. Luciferase reporter and chromatin immunoprecipitation (ChIP) were used to examine the relationship between E2F6/KDM5C and SF3A3 expression., Results: In the present study, we demonstrated that expression of SF3A3 was elevated in BC tissue compared to the normal bladder tissue. Importantly, the upregulation of SF3A3 in patients was correlated with poor prognosis. Additionally, overexpression of SF3A3 promoted while depletion of SF3A3 reduced the growth of BC cells in vivo and in vitro. Data from the TCGA database and clinical samples revealed that hypomethylation of the DNA promoter leads to high expression of SF3A3 in BC tissue. We found that upregulation of lysine-specific demethylase 5C (KDM5C) promotes SF3A3 expression via hypomethylation of the DNA promoter. The transcription factor E2F6 interacts with KDM5C, recruits KDM5C to the SF3A3 promoter, and demethylates the GpC island of H3K4me2, leading to high SF3A3 expression and BC progression., Conclusions: The results demonstrated that depletion of the KDM5C/SF3A3 prevents the growth of BC in vivo and in vitro. The E2F6/KDM5C/SF3A3 pathway may be a potential therapeutic target for BC treatment., (© 2022. The Author(s).)

Background: NPL4 is an important cofactor of the valosin-containing protein (VCP)-NPL4-UFD1 complex. The VCP-NPL4-UFD1 has been considered as a ubiquitin proteasome system (UPS) regulator and response to protein degradation. While NPL4 plays important roles in various diseases, little is known about its functions in bladder cancer (BC)., Methods: MTT assays and colony forming test were performed to evaluate cell proliferation ability and Western blotting was used to detect protein expression. Cyclin D1 mRNA expression was detected using qRT-PCR, and coimmunoprecipitation (CoIP) was used to detect protein-protein interactions., Results: NPL4 was upregulated in BC tissue and correlated with poor prognosis. Upregulation of NPL4 promoted cell proliferation while suppression of NPL4 reduced BC cell proliferation. Upregulation of NPL4 led to overexpression of cyclin D1 by enhancing its mRNA stability. Moreover, NPL4 was found to bind directly to DXO and induce its degradation. DXO was downregulated in BC tissue and regulated BC cell proliferation by destabilizing cyclin D1 mRNA. DXO-mediated NPL4 regulated BC cell proliferation by stabilizing cyclin D1 expression., Conclusions: The NPL4/DXO/cyclin D1 axis exert crucial role in BC cell growth and is associated with prognosis and may represent a potential therapeutic target for BC., Competing Interests: Competing interestsThe authors declare that they have no competing interests.