Abstract
Cancer cells adapt to nutrient-deprived tumor microenvironment during progression via regulating the level and function of metabolic enzymes. Acetyl-coenzyme A (AcCoA) is a key metabolic intermediate that is crucial for cancer cell metabolism, especially under metabolic stress. It is of special significance to decipher the role acetyl-CoA synthetase short chain family (ACSS) in cancer cells confronting metabolic stress. Here we analyzed the generation of lipogenic AcCoA in bladder cancer cells under metabolic stress and found that in bladder urothelial carcinoma (BLCA) cells, the proportion of lipogenic AcCoA generated from glucose were largely reduced under metabolic stress. Our results revealed that ACSS3 was responsible for lipogenic AcCoA synthesis in BLCA cells under metabolic stress. Interestingly, we found that ACSS3 was required for acetate utilization and histone acetylation. Moreover, our data illustrated that ACSS3 promoted BLCA cell growth. In addition, through analyzing clinical samples, we found that both mRNA and protein levels of ACSS3 were dramatically upregulated in BLCA samples in comparison with adjacent controls and BLCA patients with lower ACSS3 expression were entitled with longer overall survival. Our data revealed an oncogenic role of ACSS3 via regulating AcCoA generation in BLCA and provided a promising target in metabolic pathway for BLCA treatment.
Highlights
In cancer cells, considerable number of metabolic enzymes and intermediates are deregulated[1]
Lipogenic Acetylcoenzyme A (AcCoA) metabolism is altered in bladder urothelial carcinoma (BLCA) under stress
As AcCoA is originated from alternative pathways (Fig. 1c) and hypoxic status mimics the in vivo lipid metabolic conditions[5,6], we evaluated the fatty acids metabolism in BLCA under hypoxia
Summary
Cell culture SV-HUC-1, UMUC3, T24 cells were purchased from the American Type Culture Collection. SV-HUC-1 cell line was maintained in F-12K Medium (HyClone). UMUC3 cell line was cultured in Eagle’s Minimum Essential Medium (HyClone). T24 cell line was cultured in McCoy’s 5a Medium (HyClone). 13C Enrichment in lipogenic AcCoA detection Fatty acid labeling assay was performed as previously described[21]. We scraped cells and transferred to glass tubes, added 0.5 mL cold chloroform, and vortexed for 1 min and dried under nitrogen gas. Tube was put on ice for 5 min and 100 μl NaOH (1 M), 30 μl methyl-chloroformate were added. Histones and histone-bound acetate extraction Cells were collected and washed with cold PBS supplemented with sodium butyrate (10 mM) and nicotinamide (50 mM). Isolated histones were placed at 95 °C overnight with 10 M NaOH, added with hydrochloric acid for GC-MS
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