Dataset Information

ADH1C inhibits progression of colorectal cancer through the ADH1C/PHGDH /PSAT1/serine metabolic pathway.

ABSTRACT: Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. CRC is the second leading cause of cancer-related deaths. Although some progress in the treatment of CRC has been achieved, the molecular mechanism of CRC is still unclear. In this study, alcohol dehydrogenase 1C(ADH1C) was first identified as a target gene closely associated with the development of CRC by the comprehensive application of transcriptomics, proteomics, metabonomics and in silico analysis. The ADH1C mRNA and protein expression in CRC cell lines and tumor tissues was lower than that in normal intestinal epithelial cell lines and healthy tissues. Overexpression of ADH1C inhibited the growth, migration, invasion and colony formation of CRC cell lines and prevented the growth of xenograft tumors in nude mice. The inhibitory effects of ADH1C on CRC cells in vitro were exerted by reducing the expression of PHGDH/PSAT1 and the serine level. This inhibition could be partially reversed by adding serine to the culture medium. These results showed that ADH1C is a potential drug target in CRC.

SUBMITTER: Li S

PROVIDER: S-EPMC9525271 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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ADH1C inhibits progression of colorectal cancer through the ADH1C/PHGDH /PSAT1/serine metabolic pathway.

Li Sha S Yang Hong H Li Wan W Liu Jin-Yi JY Ren Li-Wen LW Yang Yi-Hui YH Ge Bin-Bin BB Zhang Yi-Zhi YZ Fu Wei-Qi WQ Zheng Xiang-Jin XJ Du Guan-Hua GH Wang Jin-Hua JH

Acta pharmacologica Sinica 20220330 10

Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. CRC is the second leading cause of cancer-related deaths. Although some progress in the treatment of CRC has been achieved, the molecular mechanism of CRC is still unclear. In this study, alcohol dehydrogenase 1C(ADH1C) was first identified as a target gene closely associated with the development of CRC by the comprehensive application of transcriptomics, proteomics, metabonomics ...[more]

PMID: 35354963

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Project description:Classical swine fever virus (CSFV), an obligate intracellular pathogen, hijacks cellular metabolism to evade immune surveillance and facilitate its replication. The precise mechanisms by which CSFV modulates immune metabolism remain largely unknown. Our study reveals that CSFV infection disrupts serine metabolism, which plays a crucial role in antiviral immunity. Notably, we discovered that CSFV infection leads to the deacetylation of PHGDH, a key enzyme in serine metabolism, resulting in autophagic degradation. This deacetylation impairs PHGDH's enzymatic activity, reduces serine biosynthesis, weakens innate immunity, and promotes viral proliferation. Molecularly, CSFV infection induces the association of HDAC3 with PHGDH, leading to deacetylation at the K364 site. This modification attracts the E3 ubiquitin ligase RNF125, which facilitates the addition of K63-linked ubiquitin chains to PHGDH-K364R. Subsequently, PHGDH is targeted for lysosomal degradation by p62 and NDP52. Furthermore, the deacetylation of PHGDH disrupts its interaction with the NAD+ substrate, destabilizing the PHGDH-NAD complex, impeding the active site, and thereby inhibiting de novo serine synthesis. Additionally, our research indicates that deacetylated PHGDH suppresses the mitochondria-MAVS-IRF3 pathway through its regulatory effect on serine metabolism, leading to decreased IFN-β production and enhanced viral replication. Overall, our findings elucidate the complex interplay between CSFV and serine metabolism, revealing a novel aspect of viral immune evasion through the lens of immune metabolism.ImportanceClassical swine fever (CSF) seriously restricts the healthy development of China's aquaculture industry, and the unclear pathogenic mechanism and pathogenesis of classical swine fever virus (CSFV) are the main obstacle to CSF prevention, control, and purification. Therefore, it is of great significance to explore the molecular mechanism of CSFV and host interplay, to search for the key signaling pathways and target molecules in the host that regulate the replication of CSFV infection, and to elucidate the mechanism of action of host immune dysfunction and immune escape due to CSFV infection for the development of novel CSFV vaccines and drugs. This study reveals the mechanism of serine metabolizing enzyme post-translational modifications and antiviral signaling proteins in the replication of CSFV and enriches the knowledge of CSFV infection and immune metabolism.

Dataset Information

ADH1C inhibits progression of colorectal cancer through the ADH1C/PHGDH /PSAT1/serine metabolic pathway.

Publications

ADH1C inhibits progression of colorectal cancer through the ADH1C/PHGDH /PSAT1/serine metabolic pathway.

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