DNMT1‐mediated regulating on FBXO32 promotes the progression of glioma cells through the regulation of SKP1 activity

Abstract

AbstractGlioma, a prevalent and serious form of brain cancer, is associated with dysregulation of DNA methylation, where DNA methyltransferase‐1 (DNMT1) plays a significant role in glioma progression. However, the involvement of F‐box protein 32 (FBXO32) in glioma and its regulation by DNMT1‐mediated methylation remain poorly understood. In this study, we investigated FBXO32 expression in glioma cells with high DNMT1 expression using the online dataset and correlated it with patient survival. Then impact of elevated FBXO32 expression on cell proliferation, migration, and invasion was evaluated, along with the examination of EMT‐related proteins. Furthermore, a xenograft model established by injecting glioma cells stably transfected with FBXO32 was used to evaluate tumor growth, volume, and weight. The ChIP assay was employed to study the interaction between DNMT1 and the FBXO32 promoter, revealing that DNMT1 negatively correlated with FBXO32 expression in glioma cells and promoted FBXO32 promoter methylation. Moreover, we investigated the interaction between FBXO32 and SKP1 using Co‐IP and GST pulldown assays, discovering that FBXO32 acts as an E3 ubiquitin ligase and promotes SKP1 ubiquitination, leading to its degradation. Interestingly, our findings demonstrated that high FBXO32 expression was associated with improved overall survival in glioma patients. Knockdown of DNMT1 in glioma cells increased FBXO32 expression and suppressed malignant phenotypes, suggesting that FBXO32 functions as a tumor suppressor in glioma. In conclusion, this study reveals a novel regulatory mechanism involving DNMT1‐mediated FBXO32 expression in glioma cells, where FBXO32 acts as an E3 ubiquitin ligase to degrade SKP1 via ubiquitination. This FBXO32‐mediated regulation of SKP1 activity contributes to the progression of glioma cells. These findings provide important insights into the molecular mechanisms underlying glioma progression and may hold promise for the development of targeted therapies for glioma patients.