Non-canonical function of PHGDH promotes HCC metastasis by interacting with METTL3.

PURPOSE: Phosphoglycerate dehydrogenase (PHGDH), a pivotal enzyme in serine synthesis, plays a key role in the malignant progression of tumors through both its metabolic activity and moonlight functions. This study aims to elucidate the non-canonical function of PHGDH in promoting hepatocellular carcinoma (HCC) metastasis through its interaction with methyltransferase-like 3 (METTL3), potentially uncovering a novel therapeutic target. METHODS: Western blot was used to study PHGDH expression changes under anoikis and cellular functional assays were employed to assess its role in HCC metastasis. PHGDH-METTL3 interactions were explored using GST pull-down, Co-immunoprecipitation and immunofluorescence assays. Protein stability and ubiquitination assays were performed to understand PHGDH's impact on METTL3. Flow cytometry, cellular assays and nude mice model were used to confirm PHGDH's effects on anoikis resistance and HCC metastasis in vitro and in vivo. RESULTS: PHGDH is upregulated under anoikis conditions, thereby enhancing the metastatic potential of HCC cells. By interacting with METTL3, PHGDH prevents its ubiquitin-dependent degradation, resulting in higher METTL3 protein levels. This interaction upregulates epithelial-mesenchymal transition related genes, contributing to anoikis resistance and HCC metastasis. Nude mice model confirms that PHGDH's interaction with METTL3 is crucial for driving HCC metastasis. CONCLUSION: Our research presents the first evidence that PHGDH promotes HCC metastasis by interacting with METTL3. The PHGDH-METTL3 axis may serve as a potential clinical therapeutic target, offering new insights into the multifaceted roles of PHGDH in HCC metastasis.