Background: Ubiquitin-conjugating enzyme E2 N (UBE2N) is recognized in the progression of some cancers; however, little research has been conducted to describe its role in prostate cancer. The purpose of this paper is to explore the function and mechanism of UBE2N in prostate cancer cells. Methods: UBE2N expression was detected in Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) data, prostate cancer tissue microarrays, and prostate cancer cell lines, respectively. UBE2N knockdown or overexpression was used to analyze its role in cell viability and glycolysis of prostate cancer cells and tumor growth. XAV939 or Axin1 overexpression was co-treated with UBE2N overexpression to detect the involvement of the Wnt/β-catenin signaling and Axin1 in the UBE2N function. UBE2N interacting with Axin1 was analyzed by co-immunoprecipitation assay. Results: UBE2N was upregulated in prostate cancer and the UBE2N-high expression correlated with the poor prognosis of prostate cancer. UBE2N knockdown inhibited cell viability and glycolysis in prostate cancer cells and restricted tumor formation in tumor-bearing mice. Wnt/β-catenin inhibition and Axin1 overexpression reversed the promoting viability and glycolysis function of UBE2N. UBE2N promoted Axin1 ubiquitination and decreased Axin1 protein level.

Tanshinone IIA (Tan IIA), a pleiotropic bioactive natural compound, has a general anti-tumor effect, as well as in bladder cancer. However, little is known about its mechanism. This work attempts to explore the mechanism of Tan IIA promoting cuproptosis in bladder cancer cells and the effective targets. Copper concentration and total m6A quantification were determined using test kits. Cell viability was tested by CCK-8. Gene expression was evaluated by western blot or qRT-PCR. The m6A methylation level of FDX1 was detected by methylated RNA immunoprecipitation. FDX1 3′UTR activity was evaluated by luciferase activity assay. YTHDC1 binding to FDX1 was detected by RNA immunoprecipitation assay. Inhibition of tumor growth by Tan IIA was verified using a mouse xenograft tumor model. Tan IIA inhibits cell viability and induces the expression of FDX1 and lip-DLAT, key regulators of cuproptosis, in bladder cancer cells. The copper chelator tetrathiomolybdate weakens the inhibiting effect of Tan IIA on cell viability; while Tan IIA enhances the inhibiting effect of elesclomol-Cu on cell viability. FDX1 knockdown reverses Tan IIA-induced cuproptosis. Tan IIA increases FDX1 m6A modification, which is reversed by S-adenosylhomocysteine, an inhibitor of METTL3/METTL14, and this event mediates Tan IIA-induced cuproptosis of bladder cancer cells. The effectiveness of SAH in Tan IIA promoting cuproptosis and antitumor utility is demonstrated in a xenograft tumor model. Tan IIA exerts an anti-bladder cancer effect by promoting the cuproptosis of tumor cells, and the possible mechanism is to promote the expression of FDX1 by METTL3/METTL14-mediated the increasing FDX1 m6A modification.

Traditional Chinese medicine (TCM) is widely used as an alternative therapy for cancer treatment in China. Glutamine catabolism plays an important role in cancer development. Qici Sanling decoction (QCSL) suppresses bladder cancer growth. However, the association between QCSL and glutamine catabolism remains unknown. In this study, different doses of QCSL were applied to T24 cells, followed by the measurements of cell viability and apoptosis using CCK-8 and Annexin V/PI assay, respectively. Furthermore, glutamine consumption was detected using the glutamine assay kit. QCSL was observed to inhibit cell growth and induced cell apoptosis in a dose-dependent manner. Analysis of glutamine consumption revealed that QCSL suppressed glutamine consumption in T24 cells. Furthermore, QCSL decreased the mRNA and protein levels of c-Myc, GLS1, and SLC1A5. All these effects induced by QCSL could be alleviated by c-Myc overexpression, indicating c-Myc was involved in the protective role of QCSL in bladder cancer. In addition, QCSL was found to inhibit tumor growth in the xenograft tumor model. The similar results were obtained in tumor samples that protein levels of c-Myc, GLS1, and SLC1A5 were decreased upon treatment with QCSL. In conclusion, QCSL suppresses glutamine consumption and bladder cancer cell growth through inhibiting c-Myc expression.

Bladder cancer (BCa) is one of the most common malignant tumors of the urinary system. Its frequent recurrence, high metastatic potential, and resistance to therapies pose major obstacles to achieving long-term patient survival. As a core feature of tumor metabolic reprogramming, aerobic glycolysis (the Warburg effect) plays an essential role in the development of BCa. Current studies indicate that key glycolytic enzymes such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) are abnormally expressed in BCa. These alterations in enzyme activity not only directly reshape energy metabolism but also exert non-metabolic functions, regulating tumor cell proliferation and invasion. Simultaneously, the aberrant activation of signaling pathways such as PI3K/AKT/mTOR and HIF-1α further drives the glycolytic process. Moreover, the lactate produced through glycolysis leads to tumor microenvironment (TME) acidification, which facilitates extracellular matrix remodeling and immune evasion. In terms of treatment, strategies that directly target key glycolytic enzymes and indirectly intervene in the regulation of signaling pathways show promising application potential. Nevertheless, issues related to treatment-associated toxicity and the emergence of therapeutic resistance remain unresolved. This review systematically summarizes the characteristics of key enzymes in aerobic glycolysis, molecular regulatory mechanisms, and advancements in targeted therapy for BCa, aiming to provide new theoretical insights and directions for metabolic intervention and targeted therapy in BCa.