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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1449525
This article is part of the Research Topic Application of Multi-omics Analyses in Revealing the Role of Mitochondrial Gene Defects in Disease Progression View all 9 articles

From Mitochondria to Tumor Suppression: ACAT1's Crucial Role in Gastric Cancer

Provisionally accepted
Wei He Wei He 1Yanfang Li Yanfang Li 1*Song-Bai Liu Song-Bai Liu 2*Ying Chang Ying Chang 1*Shiyuan Han Shiyuan Han 1*Xingyu Han Xingyu Han 1*Zixin Ma Zixin Ma 1*Hesham M. Amin Hesham M. Amin 3Yao-Hua Song Yao-Hua Song 1*Jin Zhou Jin Zhou 4*
  • 1 Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu Province, China
  • 2 Suzhou Key Laboratory of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, Liaoning Province, China
  • 3 Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • 4 Department of General Surgery，the First Affiliated Hospital of Soochow University, Suzhou, China

The final, formatted version of the article will be published soon.

    Acetyl CoA acetyltransferase 1 (ACAT1), a mitochondrial enzyme, is mainly involved in the formation and decomposition of ketones, isoleucine, and fatty acids. Previous clinical studies showed that mutations in the ACAT1 gene lead to ketoacidosis, Notably the role of ACAT1 in human cancer' pathogenesis varies depending on cancer type, and its specific role in gastric cancer remains largely unknown. In the current study, we found that the expression of ACAT1 in primary late-stage gastric cancer tumor tissues was significantly lower than in early-stage tumors. This observation was further confirmed in high-grade gastric cancer cell line MKN45. The expression of CD44 and OCT4 was decreased, while CD24 expression was increased by overexpressing ACAT1 in MKN45 gastric cancer cells. Moreover, the ability of gastric cancer cells to form colonies on soft agar was also reduced by ACAT1 overexpression. Likewise, overexpression of ACAT1 inhibited epithelial mesenchymal transition (EMT) in gastric cancer cells evidenced by increased expression of the epithelial marker E-Cadherin, decreased expression of mesenchymal marker vimentin, and decreased expression levels of SNAI 1/3. In addition, ACAT1 overexpression inhibited cell migration and invasion, improved the response to 5-Fluorouracil (5-FU) and etoposide. In contrast, inhibition of ACAT1 activity promoted the proliferation of gastric cancer cells. The xenotransplantation results in nude mice showed that overexpression of ACAT1 in gastric cancer cells inhibited tumor growth in vivo. In addition, the low expression of ACAT1 in gastric cancer was further validated by searching public databases and conducting bioinformatic analyses. Mechanistically, bioinformatic analysis found that the inhibitory effect of ACAT1 in gastric cancer may be related to the Adipocytokine Signaling Pathway, Ppar Signaling Pathway, Propanoate Metabolism and P53 Signaling Pathway. Correlation analysis indicated ACAT1 mRNA expression was correlated with immune infiltrates. Collectively, our data show that ACAT1 induces pronounced inhibitory effects on gastric cancer initiation and development, which may impact future strategies to treat this aggressive cancer.

    Keywords: gastric cancer, ACAT1, tumor stem cells, EMT, Mitochondrial enzyme

    Received: 15 Jun 2024; Accepted: 08 Aug 2024.

    Copyright: © 2024 He, Li, Liu, Chang, Han, Han, Ma, Amin, Song and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yanfang Li, Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu Province, China
    Song-Bai Liu, Suzhou Key Laboratory of Medical Biotechnology, Suzhou Vocational Health College, Suzhou, Liaoning Province, China
    Ying Chang, Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu Province, China
    Shiyuan Han, Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu Province, China
    Xingyu Han, Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu Province, China
    Zixin Ma, Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu Province, China
    Yao-Hua Song, Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, Jiangsu Province, China
    Jin Zhou, Department of General Surgery，the First Affiliated Hospital of Soochow University, Suzhou, China

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