The mechanistic (formally “mammalian”) target of rapamycin (mTOR) pathway serves as a crucial regulator of various biological processes such as cell growth and cancer progression. In bladder cancer, recent discoveries showing the cancer-promoting role of mTOR complex 1 have attracted wide attention. However, the regulation of mTOR signaling in bladder cancer is complicated and the underlying mechanism remains elusive. Here, we report that the deubiquitinating enzyme, ovarian tumor domain-containing protein 5 (OTUD5), can activate the mTOR signaling pathway, promote cancer progression, and show its oncogenic potential in bladder cancer. In our study, we found that OTUD5 deubiquitinated a RING-type E3 ligase, RNF186, and stabilized its function. In addition, the stabilization of RNF186 further led to the degradation of sestrin2, which is an inhibitor of the mTOR signaling pathway. Together, we provide novel insights into the pathogenesis of bladder cancer and first prove that OTUD5 can promote bladder cancer progression through the OTUD5-RNF186-sestrin2-mTOR axis, which may be exploited in the future for the diagnosis and treatment of this malignancy.

According to the World Health Organization, the incidence and mortality rates of renal cell carcinoma (RCC) are rapidly increasing worldwide. Serious side effects caused by immune therapy and resistance to targeted drug therapy are urgent clinical problems facing kidney treatment. There is increasing global interest in developing natural products with a reduced number of side effects as adjunctive therapeutic options for RCC. Ginger is a spice and herbal remedy used worldwide, and 6‐gingerol is a major pharmacologically active ingredient in ginger. In our study, we found that 6‐gingerol suppressed RCC cell migration and metastasis in vitro and in vivo. Moreover, reduction in MMP2, Slug, and Vimentin protein levels was observed following 6‐gingerol treatment of 786‐O and ACHN cells. Furthermore, we revealed the mechanisms underlying the ability of 6‐gingerol to inhibit RCC cell migration and metastasis. 6‐Gingerol increased yes‐associated protein (YAP)^ser127 phosphorylation and reduced YAP levels in cell nuclei. We also used a series of loss‐of‐function and gain‐of‐function experiments to support our results. Western blot results showed that MMP2, Slug, and Vimentin protein expression was downregulated in YAP‐silenced cells and upregulated in YAP‐overexpressing cells. Transwell data demonstrated that YAP suppressed RCC migration ability. Immunofluorescence images showed that 6‐gingerol decreased YAP levels, leading to disordered F‐actin and a reduction in cell lamellipodia. Overall, our results indicated that 6‐gingerol is a potential antimetastatic compound for use in kidney therapy.

Background: β-ionone is a terminal cyclic analog of beta-carotenoids widely found in plants. In recent years, accumulating evidence has shown that β-ionone exerts antitumor effects on various malignant tumors. However, limited studies have revealed the role of β-ionone in regulating the epithelial-mesenchymal transition (EMT) of prostate cancer (PCa) cells. This study aimed to investigate the effect of β-ionone on the EMT process of PCa, focusing on Wnt/β-catenin signaling pathway. Methods: After exposure to β-ionone, cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the Brdu proliferation assay. The Transwell and wounding healing were used to investigate the migration and invasion abilities of PCa cells. Expression of proteins involved in the EMT process (E-cadherin, N-cadherin, vimentin) and proteins in the Wnt/β-catenin pathway (β-catenin, GSK3-β, and p-GSK3-β) were explored by western blotting. The effects of β-ionone on β-catenin degradation were explored by cycloheximide tracking assay and in vitro ubiquitination assay. Nude mouse xenograft model was served as the model system in vivo. Results: The migration, invasion, and EMT process of PCa Human PC-3 prostate adenocarcinoma cells (PC3) and Human 22RV1 prostate adenocarcinoma cells (22RV1) cells were significantly inhibited after β-ionone treatment. In addition, β-ionone also inhibited the growth and EMT process of subcutaneous xenograft tumors in nude mice. The study also found that β-catenin, which promotes EMT, was downregulated after β-ionone treatment. Further mechanistic studies revealed that β-ionone inhibited the Wnt/β-catenin pathway by accelerating the ubiquitination and degradation of β-catenin in PCa, thus inhibiting the downstream migration, invasion, and EMT processes. Conclusions: These findings demonstrate that β-ionone may be a potential natural compound targeting the Wnt/β-catenin pathway for the treatment of PCa.

RBPs in the development and progression of BC remains unclear. Here, we elucidated the role of RBPs in predicting the survival of patients with BC. Clinical information and RNA sequencing data of the training and validation cohorts were downloaded from the Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. Survival-related differentially expressed RBPs were identified using Cox regression analyses. A total of 113 upregulated and 54 downregulated RBPs were observed, with six showing prognostic values (AHNAK, MAP1B, LAMA2, P4HB, FASN, and GSDMB). In both the GSE32548 and GSE31684 datasets, patients with low-risk scores in survival-related six RBPs-based prognostic model showed longer overall survival than those with high-risk scores. AHNAK, MAP1B, P4HB, and FASN expression were significantly upregulated in both BC tissues and cell lines. BC tissues from high-risk group showed higher proportions of naive CD4+ T cells, M0 and M2 macrophages, and neutrophils and lower proportions of plasma cells, CD8+ T cells, and T-cell follicular helper compared to low-risk group. AHNAK knockdown significantly inhibited the proliferation, invasion, and migration of BC cells in vitro and inhibited the growth of subcutaneous tumors in vivo. We thus developed and functionally validated a novel six RBPs-based prognostic model for BC.