On October 11, 2024, the team of Professor Wang Xinghuan of the Department of Urology, Zhongnan Hospital of Wuhan University published a report in the comprehensive journal Advanced Science (First Region Top, Chinese Academy of Sciences). Five years IF=16.3) published under the title "Deubiquitylase USP52 Promotes Bladder Cancer Progression by Modulating Ferroptosis through Stabilizing SLC7A11/xCT ".
Iron death is a new type of programmed cell death caused by the fatal accumulation of iron-dependent lipid peroxidation products. The classic System xc - /GSH/GPX4 regulatory pathway is the main antioxidant defense against iron death. System xc - is a class of cysteine/glutamate reverse transport systems widely distributed in cell membranes. It is a heterodimer composed of two subunits SLC7A11/xCT and SLC3A2. Normally, cystine is transported into the cell by System xc -, where it is reduced to cysteine for glutathione (GSH) synthesis. GSH acts as a potent reducing agent and collaborates with GPX4 to promote the reduction of LOOH to LOH, which effectively removes lipid reactive oxygen species (ROS), thereby preventing iron death.
Since it was proposed in 2012, iron death has attracted extensive attention from the academic community, and the research related to iron death has also shown exponential growth. Nevertheless, it remains unclear whether iron death plays a role in bladder cancer and whether there are key proteins in bladder cancer that determine susceptibility to iron death.
Our research team EpiTrace, a tracing technology that can trace cell age and evolution (see Nature Biotechnology | Tracing cell age and Evolution), conducted a single-cell timing analysis on bladder cancer tissues collected in different stages (see: Adv Sci | Key nodes in the epigenetic evolution of intracellular heterogeneity in bladder tumors), divided the cells into high iron death status group and low iron death status group, and found that iron death status of bladder cancer cells was negatively correlated with the stage of bladder cancer, suggesting that iron death may play an inhibitory role in the development of bladder cancer.
By screening the siRNA library of deubiquitination enzyme and using Western blot and MTT assay, we finally identified that USP52 may have the effect of stabilizing xCT protein, and then inhibit the iron death process of bladder cancer cells. Further experiments showed that USP52 knockdown can enhance cell sensitivity to iron death by reducing intracellular GSH synthesis, increasing lipid peroxidation levels and ferrous ion content, and ultimately inhibit bladder cancer progression. By mechanism, USP52 binds directly to xCT and reduces polyubiquitination of K48 ligations at lysine residues 4 and 12 in xCT proteins, thereby regulating xCT protein stability in bladder cancer. Animal studies have further demonstrated that the combination of iron death inducer and USP52 knockdown can significantly inhibit bladder cancer progression by promoting iron death. Clinically, USP52 protein is significantly highly expressed in bladder cancer tissues, and USP52 protein level is negatively correlated with the prognosis of patients with bladder cancer.
In summary, this study elucidate the mechanism by which USP52 inhibits the progression of bladder cancer by influencing iron death through regulating xCT, which is expected to provide new ideas and strategies for the clinical precision treatment of patients with bladder cancer. The first author of the paper is Jianmin Liu, a doctoral candidate in the Department of Urology at Zhongnan Hospital of Wuhan University. The research was supported by the National Natural Science Foundation of China, Hubei Provincial Department of Science and Technology, and Zhongnan Hospital of Wuhan University.
Links:
https://doi.org/10.1002/advs.202403995