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Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1

Oncogene volume 42, pages 1024–1037 (2023)Cite this article

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Abstract

Metabolic reprogram is crucial to support cancer cell growth and movement as well as determine cell fate. Mitochondrial protein acetylation regulates mitochondrial metabolism, which is relevant to cancer cell migration and invasion. The functional role of mitochondrial protein acetylation on cancer cell migration remains unclear. General control of amino acid synthesis 5 like-1(GCN5L1), as the regulator of mitochondrial protein acetylation, functions on metabolic reprogramming in mouse livers. In this study, we find that GCN5L1 expression is significantly decreased in metastatic HCC tissues. Loss of GCN5L1 promotes reactive oxygen species (ROS) generation through enhanced fatty acid oxidation (FAO), followed by activation of cellular ERK and DRP1 to promote mitochondrial fission and epithelia to mesenchymal transition (EMT) to boost cell migration. Moreover, palmitate and carnitine-stimulated FAO promotes mitochondrial fission and EMT gene expression to activate HCC cell migration. On the other hand, increased cellular acetyl-CoA level, the product of FAO, enhances HCC cell migration. Taken together, our finding uncovers the metastasis suppressor role as well as the underlying mechanism of GCN5L1 in HCC and also provides evidence of FAO retrograde control of HCC metastasis.

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Fig. 1: Deletion of GCN5L1 in HCC cells promotes cell migration and EMT.
Fig. 2: GCN5L1 controls DRP1 translocation and mitochondrial fission.
Fig. 3: GCN5L1 deletion controls DRP1-dependent mitochondrial fission to promote cell migration.
Fig. 4: Enhanced mitochondrial fission in GCN5L1 deleted cells is dependent on ROS production and ERK activation.
Fig. 5: Enhanced mitochondrial fission in GCN5L1 deleted cells is dependent on ROS production and ERK activation.
Fig. 6: Enhanced FAO promotes mitochondrial fission and cell migration in HCC.
Fig. 7: High metastatic HCC cells possess low GCN5L1 expression and high levels of DRP1-S616 phosphorylation correlating with EMT potential.

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All data generated or analyzed during this study are included in the paper and/or the Supplementary Materials. Source data are provided with this paper. Materials used in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr. Yuezhen Deng at Central South University for providing luciferase expressing Huh-7 cell line. This study was supported by grants from the National Natural Science Foundation of China (grant numbers: 92057120 and 81970674, LZ; 81902700, LW), and the Tianjin Research Innovation Project for Postgraduate Students (grant numbers: 2021YJSB276, LH; 2021YJSS151, JZ).

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Authors and Affiliations

  1. Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Linmeng Han, Chunyu Zhang, Danni Wang, Qiqi Tang & Lu Zhu

  2. Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Cell Homeostasis and Major Diseases, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Jiaqi Zhang & Lingdi Wang

  3. Department of Bioinformatics, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin, China

    Mulin Jun Li

  4. Laboratory of Mitochondrial Biology and Metabolism, NHLBI, National Institutes of Health, Bethesda, MD, USA

    Michael N. Sack

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  1. Linmeng Han
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Contributions

This study was conceived by LZ and LW; LH, LW, and LZ designed the study; Experiments were performed by LH, CZ, DW, JZ, and QT; Data were analyzed and interpreted by LH, LW and LZ; MJL supported bioinformatic analysis; MNS provided conceptual advice and revised the manuscript. The manuscript was written by LH, LW, and LZ with input from all authors.

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Correspondence to Lingdi Wang or Lu Zhu.

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Han, L., Zhang, C., Wang, D. et al. Retrograde regulation of mitochondrial fission and epithelial to mesenchymal transition in hepatocellular carcinoma by GCN5L1. Oncogene 42, 1024–1037 (2023). https://doi.org/10.1038/s41388-023-02621-w

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