Xiong Yunqiang, Dong Qianxi, Hu Hongji, Li Zhongqi, Zhan Xiangpeng, Zheng Fuchun, Wan Hao, Liu Jiahao, Wu Shuyu, Pan Wang, Yuan Ruize, Xiong Jing, Guo Ju, Xu Songhui, Fu Bin
Department of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang, Jiangxi, China.
Cell Death Dis. 2025 Jul 12;16(1):516. doi: 10.1038/s41419-025-07840-5.
Aberrant glucose metabolism, a characteristic of malignant tumors, contributes to the development and progression of bladder cancer (BCa). However, the underlying mechanism by which aberrant glucose metabolism promotes BCa progression is still incompletely understood. Here, we demonstrate that low levels of STUB1 are associated with worse progression and poor prognosis of BCa patients. STUB1 overexpression attenuates BCa cell proliferation, migration and amino acid metabolism, especial aspartate metabolism. Mechanistically, we identify that STUB1 induces K6- and K48-linked polyubiquitination of GOT2 at K73 lysine residue to decrease its stability, which attenuates mitochondrial aspartate (Asp) synthesis and regulates mitochondrial dysfunction. GOT2 was significantly up-regulated in BCa tissues and negatively associated with STUB1 expression. Furthermore, we reveal that high glucose stress promotes Asp synthesis and tumor growth through STUB1-GOT2 axis. Collectively, our findings identify that STUB1-GOT2 axis is an important regulator for maintaining Asp synthesis and mitochondrial function in BCa cell growth, which highlights that targeting STUB1-GOT2 axis could be a valuable strategy to ameliorate BCa progression by inhibiting amino acid metabolic function.
异常糖代谢是恶性肿瘤的一个特征，它促进膀胱癌（BCa）的发生和发展。然而，异常糖代谢促进BCa进展的潜在机制仍未完全阐明。在此，我们证明低水平的STUB1与BCa患者的更差进展和不良预后相关。STUB1过表达减弱BCa细胞增殖、迁移和氨基酸代谢，尤其是天冬氨酸代谢。机制上，我们发现STUB1在K73赖氨酸残基处诱导GOT2发生K6和K48连接的多聚泛素化以降低其稳定性，这减弱线粒体天冬氨酸（Asp）合成并调节线粒体功能障碍。GOT2在BCa组织中显著上调且与STUB1表达呈负相关。此外，我们揭示高糖应激通过STUB1-GOT2轴促进Asp合成和肿瘤生长。总体而言，我们的研究结果表明STUB1-GOT2轴是维持BCa细胞生长中天冬氨酸合成和线粒体功能的重要调节因子，这突出表明靶向STUB1-GOT2轴可能是通过抑制氨基酸代谢功能改善BCa进展的有价值策略。
