Multi-omics Analysis of the Role of PHGDH in Colon Cancer

Objectives: 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. Methods: 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. Results: 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. Conclusion: 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.

Abbreviations PHGDH, 3-phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; OPLS-DA, orthogonal partial least-squares discriminant analysis; TIC: total ion chromatograms.; PHGDH; acetylation modification; colon cancer; metabolomics; transcriptomics.