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ACSS2-Mediated Deacetylation of Autophagy Proteins Inhibits Malignancy of Epithelial Ovarian Cancer by Inhibiting Glycolysis
43 Pages Posted: 17 Jun 2022
More...Abstract
Background: Glycolysis and acetate metabolism are enhanced in solid tumors, including epithelial ovarian cancer (EOC). They play a role in tumorigenesis and malignancy. Studies on detailed mechanisms and hypotoxic multi-target drug development targeting glycolysis and acetate metabolism are imperative for improving therapeutic approaches.
Methods: RNA-seq, Extensively targeted metabolomic analysis, Tissue Microarray, RT-qPCR and Western Blotting were performed and identified that acyl-CoA synthetase short-chain family member 2 (ACSS2) is the key gene in glycolysis and acetate metabolism, and Paeonol, a traditional Chinese medicine monocase, is a multi-target drug. In vitro and in vivo assays were used to investigate the function of ACSS2 and Paeonol. The mechanism of ACSS2 and Paeonol were investigated by CUT &Tag analysis, Bimolecular fluorescence complementation assay, Co-IP, glucose absorption and lactate acid assays, Acetyl-CoA assessment, autophagy flux analysis and Transmission electron microscopy.
Findings: ACSS2 was upregulated and anticipated unfavorable prognosis in EOC patients. Furthermore, ACSS2 knockdown impaired the capacity of EOC cells to proliferate, migrate, and invade; angiogenesis and spherical cell formation as well as enhanced cisplatin-induced apoptosis and reduced tumor burden in vivo. Inhibition of ACSS2 not only decreased acetate metabolism but also inhibited glycolysis by targeting HK2. Reduced glycolysis, in turn, regulated the ACSS2 translocation from the cytoplasm to the nucleus, which mediated the deacetylation of autophagy proteins by promoting the expression of sirtuin-1 (SIRT1). Overactivated autophagy exerted antitumor effects by inhibiting invasion and metastasis and improving apoptosis. Paeonol can inhibit both ACSS2-mediated acetate metabolism and glycolysis to exert antitumor effects and protect hepatic and renal function.
Interpretation: We found that Paeonol can serve as an effective hypotoxic multi-target drug aimed at ACSS2 and glycolysis to exert antitumor effects against EOC via overactivation of autophagy-mediated by ACSS2–SIRT1–deacetylation signalling cascades, thus providing a novel therapeutic strategy for EOC.
Funding Information: This research is sponsored by Hubei Province's Outstanding Medical Academic Leader Programme and the Fundamental Research Funds for the Central Universities（No.2042021kf0125).
Declaration of Interests: The authors declare no competing interests.
Ethics Approval Statement: Approval of all the experiments was granted by the Renmin Hospital of Wuhan University (ethics number: 20190503).
Keywords: ACSS2, Glycolysis, Deacetylation, SIRT1, Autophagy, Paeonol, epithelial ovarian cancer
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