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.
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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

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Figure 4

PCK1 suppresses S100A11 by increasing SAM-dependent H3K9me3 occupancy.

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PCK1 suppresses S100A11 by increasing SAM-dependent H3K9me3 occupancy. (...
(A) Representative blots and densitometries of H3K9me3 and S100A11 in PKO cells and PCK1-OE cells; histone H3 and β-actin were used as loading controls (n = 3). (B) Immunofluorescent images for S100A11 in PKO cells. (C) ChIP-qPCR showing the enrichment of H3K9me3 in different promoter regions of S100A11 in PKO cells (n = 3 technical replicates). (D–F) PKO and PKO/SUVKO cells were supplemented with or without SAM for 24 hours, followed by (D) ChIP-qPCR analysis (n = 3 technical replicates), (E) qPCR assays (n = 3 technical replicates), and (F) Western blot detection (n = 3 times). Scale bars: 15 μm (B). Data are shown as the mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Tukey’s test (A and D–F). **P < 0.01, ***P < 0.001, ****P < 0.0001.