Research Paper Volume 12, Issue 9 pp 7786—7800

The positive feedback between ACSL4 expression and O-GlcNAcylation contributes to the growth and survival of hepatocellular carcinoma

Jiachen Wang 1, , Zhao Wang 1, , Jiaxiang Yuan 1, , Jiaxiang Wang 2, , Xinsheng Shen 1, ,

  • 1 Department of Minimally Invasive Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
  • 2 Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China

received: May 8, 2019 ; accepted: April 13, 2020 ; published: May 1, 2020 ;

https://doi.org/10.18632/aging.103092
How to Cite

Copyright © 2020 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Acyl-CoA ligase 4 (ACSL4) has been reported to be overexpressed in hepatocellular carcinoma (HCC) and to enhance cell proliferation. However, the molecular mechanisms underlying the role of ACSL4 in HCC progression remain largely unclear. Here, we aimed to investigate whether and how O-GlcNAcylation and ACSL4 regulate each other and HCC progression. The clinical significance of ACSL4, O-GlcNAc and GLUT1 in HCC was determined by Pearson chi-squared test and Kaplan-Meier analysis. CCK-8, flow cytometry and in vivo tumour formation assays were performed to detect cell proliferation, apoptosis and tumorigenesis. IP technology was used to evaluate the relationship between ACSL4 and O-GlcNAc. ACSL4, GLUT1 and O-GlcNAc levels were elevated in HCC tissues and predicted poor prognosis in HCC patients. ACSL4 overexpression significantly promoted cell proliferation and tumorigenesis and inhibited cell apoptosis, whereas these effects were all obviously impaired when mTOR signalling was repressed or GLUT1 was downregulated. ACSL4 could be O-GlcNAcylated, and silencing of ACSL4 abolished the effects of O-GlcNAcylation on cell growth promotion and apoptosis inhibition. Collectively, this study demonstrates that ACSL4 contributes to the growth and survival of HCC by enhancing GLUT1-mediated O-GlcNAcylation. In turn, O-GlcNAcylation promotes HCC growth partially by increasing ACSL4 expression.

Abbreviations

HCC: hepatocellular carcinoma; HBP: hexosamine biosynthetic pathway; UDP-GlcNAc: UDP-N-Acetylglucosamine; O-GlcNAc: O-linked N-acetylglucosamine; OGT: O-GlcNAc transferase; OGA: O-GlcNAcase; PuGNAc: O-(2-Acetamido-2-deoxy-D-glucopyranosyl iden amino) N phenyl carbamate (PuGNAc); GlcNAc: glucosamine; TRIB2: tribbles pseudokinase 2; ACSL4: Acyl-CoA ligase 4; CHX: cycloheximide; MEM: modified Eagle’s medium; FBS: fetal bovine serum; IP: immunoprecipitation; CCK-8: cell counting kit-8.