FBXO22 promotes glioblastoma malignant progression by mediating VHL ubiquitination and degradation.

Glioblastoma (GBM) is the most common malignant primary brain tumor. Despite comprehensive treatment with traditional surgery, radiotherapy, and chemotherapy, the median survival rate is <14.6% and the 5-year survival rate is only 5%. FBXO22, a substrate receptor of the SCF ubiquitin ligases, has been reported to play a promoting role in melanoma, liver cancer, cervical cancer, and other cancers. However, the function of FBXO22 in GBM has not been reported. In the present study, we demonstrate that FBXO22 is highly expressed in glioma and is positively correlated with worse pathological features and shorter survival of GBM patients. We revealed that FBXO22 promotes GBM cell proliferation, angiogenesis, migration, and tumorigenesis in vitro and in vivo. In terms of mechanism, we reveal that FBXO22 decreases VHL expression by directly mediating VHL ubiquitination degradation, which ultimately increases HIF-1α and VEGFA expression. In addition, our data confirm that there are positive correlations among FBXO22, HIF-1α, and VEGFA expression, and there is a negative correlation between FBXO22 and VHL protein expression in glioma patients. Our study strongly indicates that FBXO22 is a promising diagnostic marker and therapeutic target for glioma patients.

PRMT1-mediated PGK1 arginine methylation promotes colorectal cancer glycolysis and tumorigenesis.

Many types of cancer cells, including colorectal cancer cells (CRC), can simultaneously enhance glycolysis and repress the mitochondrial tricarboxylic acid (TCA) cycle, which is called the Warburg effect. However, the detailed mechanisms of abnormal activation of the glycolysis pathway in colorectal cancer are largely unknown. In this study, we reveal that the protein arginine methyltransferase 1 (PRMT1) promotes glycolysis, proliferation, and tumorigenesis in CRC cells. Mechanistically, PRMT1-mediated arginine asymmetric dimethylation modification of phosphoglycerate kinase 1 (PGK1, the first ATP-producing enzyme in glycolysis) at R206 (meR206-PGK1) enhances the phosphorylation level of PGK1 at S203 (pS203-PGK1), which inhibits mitochondrial function and promotes glycolysis. We found that PRMT1 and meR206-PGK1 expression were positively correlated with pS203-PGK1 expression in tissues from colorectal cancer patients. Furthermore, we also confirmed that meR206-PGK1 expression is positively correlated with the poor survival of patients with colorectal cancer. Our findings show that PRMT1 and meR206-PGK1 may become promising predictive biomarkers for the prognosis of patients with CRC and that arginine methyltransferase inhibitors have great potential in colorectal cancer treatment.

TRIM21 attenuates renal carcinoma lipogenesis and malignancy by regulating SREBF1 protein stability.

BACKGROUND: Metabolic reprogramming is a hallmark of various cancers. Targeting metabolic processes is a very attractive treatment for cancer. Renal cell carcinoma (RCC) is a type of metabolic disease, and the lipidomic profile of RCC is significantly altered compared with that of healthy tissue. However, the molecular mechanism underlying lipid metabolism regulation in RCC is not clear. METHODS: The XF long-chain fatty acid oxidative stress test kits were used to assess the dependence on long-chain fatty acids and mitochondrial function after knockdown TRIM21 in RCC cells. The effect of TRIM21 on the lipid content in RCC cells was determined by metabolomics analysis, Oil Red O staining, and cellular Nile red staining. qRT-PCR and western blot were used to explore the relationship between TRIM21 and lipogenesis, and then the key molecule sterol regulatory element binding transcription factor 1 (SREBF1) was identified to interact with TRIM21 by immunoprecipitation, which was also identified in an orthotopic model. Subsequently, the relevance and clinical significance of TRIM21 and SREBF1 were analyzed by The Cancer Genome Atlas (TCGA) database, and 239 tissues were collected from RCC patients. RESULTS: TRIM21 silencing attenuated the dependence of RCC cells on fatty acids, and enhanced lipid accumulation in RCC cells. TRIM21 overexpression significantly decreased lipid contents by decreasing the expression of lipogenic enzymes via ubiquitination-mediated degradation of SREBF1. SREBF1 is critical for TRIM21-mediated lipogenesis inhibition in vitro and in vivo. Moreover, TRIM21 expression is negatively correlated with SREBF1 expression, and TRIM21-SREBF1 is a reliable combinational biomarker for RCC prognosis. CONCLUSION: The findings from this study reveal a novel pathway through which TRIM21 inhibits the lipid metabolism process of RCC and shed light on the development of targeted metabolic treatment and prognosis diagnosis of RCC.

Several circulating miRNAs related to hyperlipidemia and atherosclerotic cardiovascular diseases.

BACKGROUND: In recent years, an increasing number of studies have proved that circulating miRNAs could be used for the early diagnosis of cardiovascular diseases and even play vital roles in the evaluation of therapeutic effects or prognosis. This study was conducted to examine the correlation between serum microRNAs and hyperlipidemia to provide a theoretical basis for the early screening and intervention of atherosclerotic cardiovascular diseases (ASCVD). METHODS: The serum samples and clinical data of 122 patients with hyperlipidemia and 168 healthy subjects were collected. Related clinical information was statistically analyzed for the two groups. Expression of circulating miRNAs was detected by miRNA microarray analysis and further verified by reverse transcription-quantitative PCR (RT-qPCR). RESULTS: Statistical analysis of clinical information revealed a significant difference in the incidence of ASCVD between the two groups. The MiRNA microarray analysis (n = 10) showed 22 miRNAs with significantly different expression, among which 12 showed upregulation, and the others showed downregulation. Those possessing obvious differences and stable expression in the miRNA microarray, including miRNA-191-3p, miRNA-933, and miRNA-425-3p, were chosen for further investigation using RT-qPCR. The results demonstrated that several miRNAs were related to lipid metabolism disorders, especially miRNA-933. The area under the curve (AUC) of miRNA-933 in distinguishing the hyperlipidemia and ASCVD patients was 0.739 (95% CI, 0.682-0.795; P < 0.01) and 0.703 (95% CI, 0.643-0.763, P < 0.01), respectively. CONCLUSIONS: In conclusion, miRNA-191-3p, miRNA-933, and miRNA-425-3p may be depressed in the peripheral circulation of patients with lipid metabolism disorders (mainly LDL). Circulating miRNA-933 could be a feasible predictor for ASCVD at the early stage.