Beta-elemene inhibits the growth of KDM6A-null bladder cancer cells by suppressing the epithelial-mesenchymal transition

Abstract

BackgroundBladder cancer is a highly prevalent and lethal malignant tumor characterized by frequent mutations/deletions of lysine-specific demethylase 6A (KDM6A), which is suggested to be a key event in cancer progression and metastasis. Beta-elemene has been shown to inhibit metastasis and growth of various tumors, but its effect on KDM6A-null bladder cancer cells remains unknown. ObjectiveThis study aimed to investigate the potential and molecular mechanism of β-elemene in inhibiting the growth of KDM6A-null bladder cancer. MethodsThis study examined the migration ability and viability of RT-4 (KDM6A wild-type) and KU19-19 (KDM6A-null) cell lines using wound healing assay and CCK-8, respectively. The inhibitory effect of β-elemene on KU19-19 cell migration was evaluated using transwell and immunofluorescence assays, and the expression of transfer-related proteins and genes was analyzed through western blot and qRT-PCR, respectively. Molecular docking was performed to predict the targeting of β-elemene, and the effects were confirmed in KDM6A-knockdown RT-4 cells. Finally, the therapeutic effect of β-elemene on bladder cancer was tested in animal models. ResultsThe study observed that loss of KDM6A increased bladder cancer cell migration, with KU19-19 exhibiting significantly stronger migration than RT-4. Further investigation revealed that β-elemene effectively inhibited KU19-19 cell migration, likely through targeting EZH2 as determined by molecular docking. Overexpression of KDM6A inhibited KU19-19 metastasis, while knockdown of KDM6A in RT-4 cells enhanced cell migration, which was reversed by β-elemene treatment. Notably, in vivo testing revealed a significant suppression of KU19-19 cell growth with β-elemene administered at a dosage of 100 mg/kg. Conclusionβ-elemene has the potential to suppress the growth of KDM6A-null bladder cancer by inhibiting epithelial-mesenchymal transition (EMT), which could make it a promising therapeutic option for patients with KDM6A-null bladder cancer.