2. Academic Validation
  3. Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis

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

  • Oncogene. 2020 Mar;39(11):2437-2449. doi: 10.1038/s41388-020-1156-0.
Li Gu 1 2,  Yahui Zhu 3 4,  Xi Lin 3 4,  Xingyu Tan 3 4,  Bingjun Lu 3 4,  Youjun Li 5 6
Affiliations

Affiliations

  • 1 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China. [email protected].
  • 2 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China. [email protected].
  • 3 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 4 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China.
  • 5 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China. [email protected].
  • 6 Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, China. [email protected].
PMID: 31974474 DOI: 10.1038/s41388-020-1156-0
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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