BackgroundHigh glycolysis efficiency in tumor cells can promote tumor growth. lncRNAs play an important role in the proliferation, metabolism and migration of cancer cells, but their regulation of tumor glycolysis is currently not well researched.MethodsWe analyzed the co-expression of glycolysis-related genes and lncRNAs in The Cancer Genome Atlas (TCGA) database to screen glycolysis-related lncRNAs. Further prognostic analysis and differential expression analysis were performed. We further analyzed the relationship between lncRNAs and tumor immune infiltration. Since WAC antisense RNA 1 (WAC-AS1) had the greatest effect on the prognosis among all screened lncRNAs and had a larger coefficient in the prognostic model, we chose WAC-AS1 for further verification experiments and investigated the function and mechanism of action of WAC-AS1 in hepatocellular carcinoma.ResultsWe screened 502 lncRNAs that have co-expression relationships with glycolytic genes based on co-expression analysis. Among them, 112 lncRNAs were abnormally expressed in liver cancer, and 40 lncRNAs were related to the prognosis of patients. Eight lncRNAs (WAC-AS1, SNHG3, SNHG12, MSC-AS1, MIR210HG, PTOV1-AS1, AC145207.5 and AL031985.3) were used to established a prognostic model. Independent prognostic analysis (P<0.001), survival analysis (P<0.001), receiver operating characteristic (ROC) curve analysis (AUC=0.779) and clinical correlation analysis (P<0.001) all indicated that the prognostic model has good predictive power and that the risk score can be used as an independent prognostic factor (P<0.001). The risk score and lncRNAs in the model were found to be related to a variety of immune cell infiltration and immune functions. WAC-AS1 was found to affect glycolysis and promote tumor proliferation (P<0.01). WAC-AS1 affected the expression of several glycolysis-related genes (cAMP regulated phosphoprotein 19 (ARPP19), CHST12, MED24 and KIF2A) (P<0.01). Under hypoxic conditions, WAC-AS1 regulated ARPP19 by sponging miR-320d to promote glucose uptake and lactate production (P<0.01).ConclusionWe constructed a model based on glycolysis-related lncRNAs to evaluate the prognostic risk of patients. The risk score and lncRNAs in the model were related to immune cell infiltration. WAC-AS1 can regulate ARPP19 to promote glycolysis and proliferation by sponging miR-320d.

Suppressor of variegation, Enhancer of Zeste, Trithorax and Myeloid-Nervy-DEAF1 domain-containing (SMYD) proteins are a set of lysine methyltransferases involved in a range of diverse biological functions, including gene expression, and regulation of skeletal and cardiac-muscle development. These proteins may additionally serve roles in a number of different types of cancer. However, the roles of the five SMYD proteins, SMYD 1/2/3/4/5, their expression patterns and prognostic value remain unclear. In the present study, the transcriptional expression levels of the five SMYD proteins were compared with the survival data of patients with breast carcinoma (BC) from the ONCOMINE dataset, Breast Cancer Gene-Expression Miner v4.0, Kaplan-Meier Plotter, The Cancer Genome Atlas and cBioPortal. An increase in the SMYD2/3/5 mRNA expression levels and a decrease in SMYD1/4 mRNA expression levels in BC tissues compared with normal tissues were identified. Increased SMYD3 mRNA and decreased SMYD5 mRNA expression levels were associated with decreased levels of histological differentiation, according to the Scarff-Bloom-Richardson grading system. Kaplan-Meier curves demonstrated that the increased SMYD1/4 and decreased SMYD2/3 mRNA expression levels were associated with good relapse-free survival (RFS) in patients with BC. Furthermore, SMYD2 mRNA expression levels were associated with the RFS of patients with BC with metastatic relapse, and SMYD4 may serve as a tumor suppressor in patients with BC, as patients with increased SMYD4 mRNA expression levels had significantly better RFS compared with decreased SMYD4 mRNA expression levels. The present data suggested that SMYD2 and SMYD3 may be potential biomarkers for diagnosis of BC. Additionally, SMYD2 and SMYD4 may be potential prognostic indicators of patients with BC.

Mitochondrial dysfunction and glycolysis activation are improtant hallmarks of hepatocellular carcinoma (HCC). NOP2 is an S-adenosyl-L-methionine-dependent methyltransferase that regulates the cell cycle and proliferation activities. In this study, found that NOP2 contributes to HCC progression by promoting aerobic glycolysis. Our results revealed that NOP2 was highly expressed in HCC and that it was associated with unfavorable prognosis. NOP2 knockout in combination with sorafenib enhanced sorafenib sensitivity, which, in turn, led to marked tumor growth inhibition. Mechanistically, we identified that NOP2 regulates the c-Myc expression in an m5C-modification manner to promote glycolysis. Moreover, our results revealed that m5C methylation induced c-Myc mRNA degradation in an eukaryotic translation initiation factor 3 subunit A (EIF3A)-dependent manner. In addition, NOP2 was found to increase the expression of the glycolytic genes LDHA, TPI1, PKM2, and ENO1. Furthermore, MYC associated zinc finger protein (MAZ) was identified as the major transcription factor that directly controlled the expression of NOP2 in HCC. Notably, in a patient-derived tumor xenograft (PDX) model, adenovirus-mediated knockout of NOP2 maximized the antitumor effect and prolonged the survival of PDX-bearing mice. Our cumulative findings revealed the novel signaling pathway MAZ/NOP2/c-Myc in HCC and uncovered the important roles of NOP2 and m5C modifications in metabolic reprogramming. Therefore, targeting the MAZ/NOP2/c-Myc signaling pathway is suggested to be a potential therapeutic strategy for the treatment of HCC.

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