RASGEF1B suppresses hepatocellular carcinoma through the ALDH7A1/Betaine/SNAI1 metabolic‒epigenetic axis.
[BACKGROUND] Metabolic‒epigenetic crosstalk critically orchestrates hepatocellular carcinoma (HCC) pathogenesis.
APA
Guo Z, Tan K, et al. (2026). RASGEF1B suppresses hepatocellular carcinoma through the ALDH7A1/Betaine/SNAI1 metabolic‒epigenetic axis.. Journal of translational medicine, 24(1). https://doi.org/10.1186/s12967-026-07785-z
MLA
Guo Z, et al.. "RASGEF1B suppresses hepatocellular carcinoma through the ALDH7A1/Betaine/SNAI1 metabolic‒epigenetic axis.." Journal of translational medicine, vol. 24, no. 1, 2026.
PMID
41742192
Abstract
[BACKGROUND] Metabolic‒epigenetic crosstalk critically orchestrates hepatocellular carcinoma (HCC) pathogenesis. Deciphering the precise mechanism underlying epigenetic remodeling and metabolic reprogramming in HCC may lead to novel treatment paradigms, however, the key mechanisms remain elusive.
[METHODS] RT-qPCR, western blotting and tissue microarrary Immunohistochemistry were used to detect the expression of RasGEF domain family member 1B (RASGEF1B) in HCC and normal liver tissues. Transcriptome sequencing and high-resolution untargeted metabolomics were integrated to identify the downstream regulatory mechanism through which RASGEF1B inhibited the HCC progression. Epigenetic regulation was investigated using methylation-specific PCR and luciferase reporter assays. Bioinformatic prediction and molecular docking suggested a functional interplay among RASGEF1B, ALDH7A1, and BMI1, which was experimentally confirmed through coimmunoprecipitation, GST pull-down, and immunofluorescence assays. Protein stability and ubiquitination status of ALDH7A1 were examined using cycloheximide, immunoprecipitation assay, and an in vitro reconstituted ubiquitination system.
[RESULTS] In this study, the antitumor role of RASGEF1B was confirmed in vitro and in vivo. Transcriptomic profiling revealed that RASGEF1B overexpression significantly reduced the snail family transcriptional repressor 1 (SNAI1), a master regulator of the epithelial-mesenchymal transition. Untargeted metabolomics revealed that RASGEF1B promoted SNAI1 DNA methylation through Betaine-mediated methionine metabolic reprogramming. Further analysis confirmed that RASGEF1B competitively protected the ALDH7A1 protein from BMI1-dependent ubiquitination, thereby elevating cellular Betaine levels in HCC.
[CONCLUSIONS] This study revealed that RASGEF1B inhibited SNAI1 to suppress HCC through metabolite‒epigenetic crosstalk. Our findings potentially offer a new perspective on the classical RAS signaling framework, uncovering a metabolic‒epigenetic axis as an innovative therapeutic approach for improving clinical outcomes in patients with HCC.
[GRAPHICAL ABSTRACT] [Image: see text]
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-026-07785-z.
[METHODS] RT-qPCR, western blotting and tissue microarrary Immunohistochemistry were used to detect the expression of RasGEF domain family member 1B (RASGEF1B) in HCC and normal liver tissues. Transcriptome sequencing and high-resolution untargeted metabolomics were integrated to identify the downstream regulatory mechanism through which RASGEF1B inhibited the HCC progression. Epigenetic regulation was investigated using methylation-specific PCR and luciferase reporter assays. Bioinformatic prediction and molecular docking suggested a functional interplay among RASGEF1B, ALDH7A1, and BMI1, which was experimentally confirmed through coimmunoprecipitation, GST pull-down, and immunofluorescence assays. Protein stability and ubiquitination status of ALDH7A1 were examined using cycloheximide, immunoprecipitation assay, and an in vitro reconstituted ubiquitination system.
[RESULTS] In this study, the antitumor role of RASGEF1B was confirmed in vitro and in vivo. Transcriptomic profiling revealed that RASGEF1B overexpression significantly reduced the snail family transcriptional repressor 1 (SNAI1), a master regulator of the epithelial-mesenchymal transition. Untargeted metabolomics revealed that RASGEF1B promoted SNAI1 DNA methylation through Betaine-mediated methionine metabolic reprogramming. Further analysis confirmed that RASGEF1B competitively protected the ALDH7A1 protein from BMI1-dependent ubiquitination, thereby elevating cellular Betaine levels in HCC.
[CONCLUSIONS] This study revealed that RASGEF1B inhibited SNAI1 to suppress HCC through metabolite‒epigenetic crosstalk. Our findings potentially offer a new perspective on the classical RAS signaling framework, uncovering a metabolic‒epigenetic axis as an innovative therapeutic approach for improving clinical outcomes in patients with HCC.
[GRAPHICAL ABSTRACT] [Image: see text]
[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12967-026-07785-z.
같은 제1저자의 인용 많은 논문 (5)
- Discovery of novel and potent 2-aminopyrazine-based HPK1 inhibitors enhancing T-cell immunity against cancer.
- Mitochondria Pathway Signature Predicts Prognosis and Therapeutic Response and Identifies REXO2 as a Crucial Regulator in Breast Cancer.
- The microbial metabolite I3A inhibits ferroptosis and the effectiveness of redox-based cancer therapy.
- Correction: Guo et al. Shikonin as a WT1 Inhibitor Promotes Promyeloid Leukemia Cell Differentiation. 2022, , 8264.
- Artificial intelligence in oncological imaging screening.