Metabolic reprogramming is a vital factor in the development of many types of cancer, including colon cancer. Serine metabolic reprogramming is a major feature of tumor metabolism. Yes-associated protein (YAP) participates in organ size control and tumorigenesis. However, the relationship between YAP and serine metabolism in colon cancer is unclear. In this study, RNA sequencing and metabolomics analyses indicated significant enrichment of the glycine, serine, and threonine metabolism pathways in serine starvation–resistant cells. Short-term serine deficiency inhibited YAP activation, whereas a prolonged response dephosphorylated YAP and promoted its activity. Mechanistically, USP7 increases YAP stability under increased serine conditions by regulating deubiquitination. Verteporfin (VP) effectively inhibited the proliferation of colon cancer cells and organoids and could even modulate serine metabolism by inhibiting USP7 expression. Clinically, YAP was significantly activated in colon tumor tissues and positively correlated with the expression of phosphoglycerate dehydrogenase (PHGDH) and USP7. Generally, our study uncovered the mechanism by which serine metabolism regulates YAP via USP7 and identified the crucial role of YAP in the regulation of cell proliferation and tumor growth; thus, VP may be a new treatment for colon cancer.

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Methionine is one of the essential amino acids. How tumor cells adapt and adjust their signal transduction networks to avoid apoptosis in a methionine-restricted environment is worthy of further exploration. In this study, we investigated the molecular mechanism of glioma response to methionine restriction, providing a theoretical basis for new treatment strategies for glioma.MethodsWe constructed methionine-restriction-tolerant cells in order to study the response of glioma to a methionine-restricted environment. The transcriptome analysis of the tolerant cells showed significant changes in MAT2A. Western blotting, immunohistochemistry, quantitative real-time PCR, colony formation assays, and other experiments were used to verify the role of MAT2A in glioma genesis. In addition, the regulatory mechanism of MAT2A mRNA nuclear export was investigated by transfection, plasma nucleation separation, and co-immunoprecipitation.ResultsUnder methionine restriction, glioma cells showed high expression of MAT2A, and an inhibitor of MAT2A reduced the proliferation of tumor cells. The expression of MAT2A was positively correlated with World Health Organization-grade glioma. High expression of MAT2A was related to increased transfer of its mRNA out of the nucleus. The expression of nuclear export regulatory molecule MTR4 could affect the export of MAT2A mRNA. In a methionine-restricted environment, ubiquitination of MTR4 was enhanced, and thus its protein level was reduced. The E3 ubiquitin ligase was verified to be SYVN1.ConclusionIn summary, methionine restriction leads to increased ubiquitination of MTR4, which promotes the transfer of MAT2A mRNA out of the nucleus and MAT2A protein expression. MAT2A promotes histone methylation, prompting cells to proliferate in a methionine-restricted environment.