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Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis

Oncogene volume 39, pages 2437–2449 (2020)Cite this article

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Abstract

Metabolic alteration for adaptation of the local environment has been recognized as a hallmark of cancer. GNPAT dysregulation has been implicated in hepatocellular carcinoma (HCC). However, the precise posttranslational regulation of GNPAT is still undiscovered. Here we show that ACAT1 is upregulated in response to extra palmitic acid (PA). ACAT1 acetylates GNPAT at K128, which represses TRIM21-mediated GNPAT ubiquitination and degradation. Conversely, GNPAT deacetylation by SIRT4 antagonizes ACAT1’s function. GNPAT represses TRIM21-mediated FASN degradation and promotes lipid metabolism. Furthermore, shRNA-mediated ACAT1 ablation and acetylation deficiency of GNPAT repress lipid metabolism and tumor progression in xenograft and DEN/CCl4-induced HCC. Otherwise, ACAT1 inhibitor combination with sorafenib enormously retards tumor formation in mice. Collectively, we demonstrate that stabilization of FASN by ACAT1-mediated GNPAT acetylation plays a critical role in hepatocarcinogenesis.

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Fig. 1: ACAT1 acetylates GNPAT.
Fig. 2: SIRT4 deacetylates GNPAT at K128.
Fig. 3: ACAT1 stabilizes GNPAT by its acetylation at K128.
Fig. 4: GNPAT acetylation impairs TIRM21-mediated ubiquitination and degradation.
Fig. 5: GNPAT represses TRIM21-mediated FASN degradation and promotes lipogenesis.
Fig. 6: ACAT1-mediated GNPAT acetylation promotes tumor growth.
Fig. 7: ACAT1 inhibition and GNPAT acetylation attenuates and enhances DEN/CCl4-induced hepatocarcinogenesis in mice, respectively.
Fig. 8: Suppression of DEN/CCL4-induced hepatocarcinogenesis by combination of sorafenib and ACAT1 inhibitor in mice.

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Acknowledgements

We thank Profs Qunying Lei (Fudan University, Shanghai) for the SIRT family vectors and FASN plasmid, Yan Wang (Wuhan University, Wuhan, China) for the AAV8 vector, Ping Wang (East China Normal University, Shanghai, China) for pcDNA3.1(+)-5′flag Luc vector and Jinxiang Zhang (Wuhan Union Hospital, Wuahn, China) for providing the HCC samples. This work was supported by grants from the National Nature Science Foundation of China (81772609, 81902843), Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (TFJC2018005), and China Postdoctoral Science Foundation (2019T120681, 2019M652702).

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  1. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Li Gu, Yahui Zhu, Xi Lin, Xingyu Tan, Bingjun Lu & Youjun Li

  2. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China

    Li Gu, Yahui Zhu, Xi Lin, Xingyu Tan, Bingjun Lu & Youjun Li

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Gu, L., Zhu, Y., Lin, X. et al. Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis. Oncogene 39, 2437–2449 (2020). https://doi.org/10.1038/s41388-020-1156-0

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