Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression
Dongmei Gou, … , Kai Wang, Ni Tang
Dongmei Gou, … , Kai Wang, Ni Tang
Published May 11, 2023
Citation Information: J Clin Invest. 2023;133(13):e161713. https://doi.org/10.1172/JCI161713.
View: Text | PDF
Research Article Metabolism Oncology

Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression

Abstract

Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to the suppression of the oncogene S100A11. Mechanistically, PCK1 deficiency–induced oncogenic activation of S100A11 was due to its interaction with AKT1, which upregulated PI3K/AKT signaling. Intriguingly, the progression of hepatocellular carcinoma (HCC) driven by PCK1 deficiency was suppressed by SAM supplement or S100A11 KO in vivo and in vitro. These findings reveal the availability of the key metabolite SAM as a bridge connecting the gluconeogenic enzyme PCK1 and H3K9 trimethylation in attenuating HCC progression, thus suggesting a potential therapeutic strategy against HCC.

Authors

Dongmei Gou, Rui Liu, Xiaoqun Shan, Haijun Deng, Chang Chen, Jin Xiang, Yi Liu, Qingzhu Gao, Zhi Li, Ailong Huang, Kai Wang, Ni Tang

×

Figure 1

PCK1 upregulates H3K9me3 levels and provides methyl donors by enhancing SSP flux.

Options: View larger image (or click on image) Download as PowerPoint
PCK1 upregulates H3K9me3 levels and provides methyl donors by enhancing ...
(A) Immunoblots of the indicated proteins or histone modification markers in PCK1-KO PLC/PRF/5 cells (PKO cells) and PCK1-KO SNU449 cells (PKO cells). Data from 1 representative experiment are shown (n = 3). (B) Western blots from SK-Hep1 cells and MHCC97H cells overexpressing GFP (control cells), WT PCK1, or an enzymatically deficient mutant (PCK1 G309R). Mock-treated cells served as a blank control. Data from 1 representative experiment are shown (n = 3). (C) Immunoblots in liver tumors from DEN/CCl4-induced WT and LKO mice and densitometric analysis of H3K9me3 (n = 6 mice per group). (D) Enrichment bubble metabolic pathways, (E) heatmap showing changes in biosynthesis of amino acids, and (F) fold changes in intermediate metabolites of the SSP in SK-Hep1 cells overexpressing WT PCK1 (n = 6 biologically independent samples). 2PG, 2-phosphoglycerate. (G and H) LC-MS analysis of intracellular metabolites in (G) PKO cells and (H) PCK1-OE cells (n = 6 biologically independent samples). Data are shown as the mean ± SEM. Statistical analysis was performed using 2-tailed unpaired Student’s t test (C and F) or 1-way ANOVA with Tukey’s test (A, B, G, and H). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.