Pharmacological inhibition of BUB1 suppresses UCEC progression by modulating the PI3K-AKT pathway and reversing anoikis resistance and immune evasion: a multi-omics and experimental study

Abstract

Uterine corpus endometrial carcinoma (UCEC) is a prevalent gynecological malignancy with poor prognosis and limited therapeutic strategies. The mitotic checkpoint kinase BUB1 has emerged as a potential regulator of tumor progression, but its clinical and functional roles in UCEC remain unclear. Transcriptomic datasets from TCGA and GEO were analyzed to evaluate BUB1 expression, survival impact, pathway enrichment, methylation, and immune infiltration. Protein–protein interactions and drug sensitivity analyses were performed using bioinformatics pipelines. Functional validation was conducted in HEC-1-B cells treated with the BUB1 inhibitor 2OH-BNPP1 using MTT, wound healing, and qPCR assays. BUB1 was significantly upregulated in UCEC tumors compared with normal endometrium, associated with advanced disease stage and reduced overall survival, confirming its role as an unfavorable prognostic biomarker. Enrichment analyses linked BUB1 to cell cycle regulation, PI3K-AKT signaling, and anoikis resistance. BUB1 expression positively correlated with infiltration of macrophages, neutrophils, and CD4⁺ T cells. Pharmacological inhibition with 2OH-BNPP1 reduced cell viability, impaired migration, and suppressed BUB1 expression in a dose-dependent manner, supporting its oncogenic role in endometrial carcinoma. This study identifies BUB1 as a clinically relevant prognostic biomarker and therapeutic target in UCEC. Targeting BUB1 interrupts tumor-promoting processes including proliferation, survival, and migration, underscoring its translational potential for future therapeutic development. BUB1 is significantly overexpressed in UCEC and correlates with poor survival and advanced tumor stage. BUB1 promotes anoikis resistance and may drive metastatic potential in UCEC cells. Hypomethylation, SNV and CNVs contribute to the overexpression of BUB1 in UCEC tumors. BUB1 expression is positively associated with immunosuppressive cell infiltration. 2OH BNPP1 inhibits BUB1, thereby reducing the viability and migration of UCEC cells in vitro. BUB1 is significantly overexpressed in UCEC and correlates with poor survival and advanced tumor stage. BUB1 promotes anoikis resistance and may drive metastatic potential in UCEC cells. Hypomethylation, SNV and CNVs contribute to the overexpression of BUB1 in UCEC tumors. BUB1 expression is positively associated with immunosuppressive cell infiltration. 2OH BNPP1 inhibits BUB1, thereby reducing the viability and migration of UCEC cells in vitro.