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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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 5

PCK1 deficiency induces HCC cell proliferation, migration, and tumorigenesis via S100A11.

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PCK1 deficiency induces HCC cell proliferation, migration, and tumorigen...
(A) Western blot showing the protein expression from PCK1/S100A11 double-KO PLC/PRF/5 cells (PKO/S100-KO cells). Numbers that appear below the blots represent the relative densities (measured using ImageJ software) of S100A11 protein bands normalized to β-actin, or the relative densities of H3K9me3 modification normalized to histone H3. (B) Cell proliferation (n = 3 technical replicates) and (C) colony formation assays, Transwell assays, and wound-healing assays (n = 3 biologically independent samples) in PKO/S100-KO cells. (D) Gross images, (E) liver weight, (F) tumor number, and (G) H&E staining in the orthotopic HCC model, as indicated (n = 6 mice per group). (H) H&E staining analysis and (I) quantification of metastatic nodules in the lung metastasis model (n = 6 mice per group). Scale bars: 100 μm (G and H). Data are shown as the mean ± SEM. Statistical analysis was performed using 1-way ANOVA with Tukey’s test (C, E, F, and I) and 2-way ANOVA with Bonferroni’s test (B). *P < 0.05, **P < 0.01, ***P < 0.001.