A hallmark of tumor cells, including bladder cancer (BLCA) cells, is metabolic reprogramming toward aerobic glycolysis (Warburg effect). The classical oncogene MYC, which is crucial in regulating glycolysis, is amplified and activated in BLCA. However, direct targeting of the c-Myc oncoprotein, which regulates glycolytic metabolism, presents great challenges and necessitates the discovery of a more clarified regulatory mechanism to develop selective targeted therapy. In this study, a siRNA library targeting deubiquitinases identified a candidate enzyme named USP43, which may regulate glycolytic metabolism and c-Myc transcriptional activity. Further investigation using functional assays and molecular studies revealed a USP43/c-Myc positive feedback loop that contributes to the progression of BLCA. Moreover, USP43 stabilizes c-Myc by deubiquitinating c-Myc at K148 and K289 primarily through deubiquitinase activity. Additionally, upregulation of USP43 protein in BLCA increased the chance of interaction with c-Myc and interfered with FBXW7 access and degradation of c-Myc. These findings suggest that USP43 is a potential therapeutic target for indirectly targeting glycolytic metabolism and the c-Myc oncoprotein consequently enhancing the efficacy of bladder cancer treatment.

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor that the underlying molecular mechanisms are largely unclear. This study aimed to elucidate the key candidate genes and pathways in ccRCC by integrated bioinformatics analysis. 1387 differentially expressed genes were identified based on three expression profile datasets, including 673 upregulated genes and 714 downregulated genes. Then we used weighted correlation network analysis to identify 6 modules associated with pathological stage and grade, blue module was the most relevant module. GO and KEGG pathway analyses showed that genes in blue module were enriched in cell cycle and metabolic related pathways. Further, 25 hub genes in blue module were identified as hub genes. Based on GEPIA database, 9 genes were associated with progression and prognosis of ccRCC patients, including PTTG1, RRM2, TOP2A, UHRF1, CEP55, BIRC5, UBE2C, FOXM1 and CDC20. Then multivariate Cox regression showed that the risk score base on 9 key genes signature was a clinically independent prognostic factor for ccRCC patients. Moreover, we screened out several new small molecule drugs that have the potential to treat ccRCC. Few of them were identified as biomarkers in ccRCC. In conclusion, our research identified 9 potential prognostic genes and several candidate small molecule drugs for ccRCC treatment.

Epidermal growth factor-containing fibulin-like extracellular matrix protein 2 (EFEMP2), an extracellular matrix protein, is highly associated with tumor invasion and metastasis. However, influenced by the tumor microenvironment, EFEMP2 played different roles in different tumors. The current study focused on exploring the role of EFEMP2 in bladder cancer (BCa). The results suggested that the expression of EFEMP2 was significantly higher in normal tissues and cells compared with BCa samples and cells. And we found a negative correlation between EFEMP2 expression and high tumor stage, high tumor grade, patients with low EFEMP2 expression had a much poorer survival than those patients with high EFEMP2 expression. The multivariate analysis revealed that low EFEMP2 expression was a high-risk predictor of BCa survival. Furthermore, cell proliferation, migration and metastasis can be obviously affected by the changes of EFEMP2 expression both in vitro and in vivo. Our results also turned out that knockdown of EFEMP2 could significantly reduce the epithelial marker (E-cadherin), increase mesenchymal markers (N-cadherin, Vimentin, Snail and Slug) as well as the key factors of Wnt/β-catenin signaling pathway (β-catenin, c-Myc and cyclin D1). The reversed results were found in the EFEMP2 overexpression cells. Importantly, the related expression changes of epithelial-mesenchymal transition (EMT) markers and Wnt/β-catenin signaling pathway factors induced by EFEMP2 upregulation or downregulation can be rescued using LiCl or XAV939. Collectively, our observations revealed that EFEMP2 is a blocker of tumor progression and metastasis in BCa.

UPP1, a crucial pyrimidine metabolism-related enzyme, catalyzes the reversible phosphorylation of uridine to uracil and ribose-1-phosphate. However, the effects of UPP1 in bladder cancer (BLCA) have not been elucidated. AKT, which is activated mainly through dual phosphorylation (Thr308 and Ser473), promotes tumorigenesis by phosphorylating downstream substrates. This study demonstrated that UPP1 promotes BLCA cell proliferation, migration, invasion, and gemcitabine resistance by activating the AKT signaling pathway in vitro and in vivo. Additionally, UPP1 promoted AKT activation by facilitating the binding of AKT to PDK1 and PDK2 and the recruitment of phosphatidylinositol 3,4,5-triphosphate to AKT. Moreover, the beneficial effects of UPP1 on BLCA tumorigenesis were mitigated upon UPP1 mutation with Arg94 or MK2206 treatment (AKT-specific inhibitor). AKT overexpression or SC79 (AKT-specific activator) treatment restored tumor malignancy and drug resistance. Thus, this study revealed that UPP1 is a crucial oncogene and a potential therapeutic target for BLCA and that UPP1 activates the AKT signaling pathway and enhances tumorigenesis and drug resistance to gemcitabine.