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Multi-omics Analysis of the Role of PHGDH in Colon Cancer
Zhihui Dai1,2, Lin Chen3, KaiLing Pan3
1Department of General Surgery, 105860The Second Affiliated Hospital of Soochow University, Suzhou, China.
Abstract:
Serine metabolism is essential for tumor cells. Endogenous serine arises from de novo synthesis pathways. As the rate-limiting enzyme of this pathway, PHGDH is highly expressed in a variety of tumors including colon cancer. Therefore, targeted inhibition of PHGDH is an important strategy for anti-tumor therapy research. However, the specific gene expression and metabolic pathways regulated by PHGDH in colon cancer are still unclear. Our study was aimed to clarified the role of PHGDH in serine metabolism in colon cancer to provide new knowledge for in-depth understanding of serine metabolism and PHGDH function in colon cancer. In this study, we analyzed the gene expression and metabolic remodeling process of colon cancer cells (SW620) after targeted inhibition of PHGDH by gene transcriptomics and metabolomics. LC-MS analysis was performed in 293T cells to PHGDH gene transcription and protein post-translational modification under depriving exogenous serine. We found that amino acid transporters, amino acid metabolism, lipid synthesis related pathways compensation and other processes are involved in the response process after PHGDH inhibition. And ATF4 mediated the transcriptional expression of PHGDH under exogenous serine deficiency conditions. While LC-MS analysis of post-translational modification revealed that PHGDH produced changes in acetylation sites after serine deprivation that the K289 site was lost, and a new acetylation site K21was produced. Our study performed transcriptomic and metabolomic analysis by inhibiting PHGDH, thus clarifying the role of PHGDH in gene transcription and metabolism in colon cancer cells. The mechanism of high PHGDH expression in colon cancer cells and the acetylation modification that occurs in PHGDH protein were also clarified by serine deprivation. In our study, the role of PHGDH in serine metabolism in colon cancer was clarified by multi-omics analysis to provide new knowledge for in-depth understanding of serine metabolism and PHGDH function in colon cancer.
Insights
Targeting PHGDH, crucial for tumor cell serine metabolism, reveals compensatory pathways and ATF4 regulation in colon cancer. Serine deprivation alters PHGDH acetylation, offering new therapeutic insights.
Area of Science:
- Biochemistry
- Oncology
- Metabolomics
Background:
- Serine metabolism is vital for tumor cell growth, with PHGDH as a key enzyme in its de novo synthesis.
- High PHGDH expression is observed in various cancers, including colon cancer, making it a therapeutic target.
- The precise gene expression and metabolic pathways influenced by PHGDH in colon cancer remain incompletely understood.
Purpose of the Study:
- To elucidate the role of PHGDH in serine metabolism within colon cancer.
- To investigate the gene expression and metabolic alterations following PHGDH inhibition in colon cancer cells.
- To explore the regulatory mechanisms of PHGDH, including transcriptional control and post-translational modifications.
Main Methods:
- Gene transcriptomics and metabolomics analyses were performed on SW620 colon cancer cells after PHGDH inhibition.
- LC-MS was used to analyze PHGDH gene transcription and protein post-translational modifications in 293T cells under serine deprivation.
- Multi-omics approaches were employed to comprehensively assess PHGDH's function.
Main Results:
- PHGDH inhibition triggered compensatory responses involving amino acid transporters, amino acid metabolism, and lipid synthesis pathways.
- ATF4 was identified as a mediator of PHGDH transcriptional expression under conditions of exogenous serine deficiency.
- Serine deprivation led to changes in PHGDH acetylation, including the loss of the K289 site and the appearance of a new K21 acetylation site.
Conclusions:
- This study clarifies PHGDH's role in colon cancer gene transcription and metabolism through transcriptomic and metabolomic analyses.
- The mechanisms underlying high PHGDH expression in colon cancer and its acetylation modifications under serine deprivation were elucidated.
- The findings provide novel insights into serine metabolism and PHGDH function in colon cancer, potentially informing future therapeutic strategies.
