RETRACTED ARTICLE: Acetyl-CoA synthetase 3 promotes bladder cancer cell growth under metabolic stress

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.

Genomic and transcriptomic landscape of conjunctival melanoma

“…Furthermore, silencing of ACSS2 in mouse models of liver cancer leads to dramatic reduction of tumor growth [ 63 ]. Recently, expression of ACSS3 has also been reported in association with cancer growth and invasion in human gastric cancer and bladder urothelial carcinoma [ 64 , 65 ]. All these data indicate that ACSS3 may represent an interesting candidate for tumorigenesis of CJM and that p.P532S could act as an activating driver mutation.…”

Endoplasmic Reticulum Stress and Tumor Microenvironment in Bladder Cancer: The Missing Link

“…At the same time, tumor cells competitively inhibit the sugar metabolism of immune cells in the microenvironment, thus creating a local acidic microenvironment. This microenvironment not only hampers the clearance of bladder cancer by immune cells, but also promotes tumor proliferation and invasion by fostering neovascularization (Afonso et al, 2020;Zhang et al, 2020).…”

Acetate Revisited: A Key Biomolecule at the Nexus of Metabolism, Epigenetics, and Oncogenesis – Part 2: Acetate and ACSS2 in Health and Disease

“…The role of ACSS3 in the generation of lipogenic acetyl-CoA has been examined in bladder urothelial carcinoma cells (BLCA) under metabolic stress. ACSS2 and ACSS3 protein expression levels were increased in vitro by reduced serum and reduced oxygen, whereas the expression of ACSS1 was not changed by either one ( Zhang et al, 2020 ). Knockdown of ACSS3 in these cells resulted in reduced labeling of fatty acids from radiolabeled acetate, suggesting that ACSS3 provided acetyl-CoA for lipid synthesis.…”

“…Further, histone acetylation was reduced by ACSS3 knockdown. Both of these studies ( Chang et al, 2018 ; Zhang et al, 2020 ) implicated mitochondrial ACSS3 with the generation of acetyl-CoA in the cytoplasm and nucleus. This could be accomplished if the acetyl-CoA generated by ACSS3 was utilized by citrate synthase, followed by export of citrate to the cytoplasm and then the nucleus.…”