Introduction & Objectives: Bladder cancer (BCa) is a common urologic malignancy characterized by poor prognosis. Abnormal metabolism and its key genes play a critical role in BCa progression. In this study, we report the role of phosphoglycerol dehydrogenase (PHGDH), a key molecule of serine metabolism, in regulating ferroptosis in BCa.
Materials & Methods: BCa tissues of 90 patients were analyzed by RNA-sequencing for differential pathways and genes. Western blot, qPCR and IHC were used to detect PHGDH expression in cell lines (in vitro) and patient tissues (in vivo). R software was used to analyze PHGDH expression, prognosis and PHGDH+SLC7A11 score. The biological functions of PHGDH were investigated through organoids, and in vitro and in vivo experiments. C11 probes, bioelectron microscopy and ferroptosis inhibitors/inducers were used to detect cellular ferroptosis levels. Protein profiling, co-IP and RIP assays were used to screen proteins that might bind to PHGDH. PHGDH-targeted inhibitor NCT-502 was used to evaluate its effect on BCa cells
Results: PHGDH was highly expressed in patients with BCa. Knock-down of PHGDH promoted ferroptosis, while decreased proliferation of BCa cells. Additionally, PHGDH knock-down downregulated the expression of SLC7A11. Co-IP and mass spectrometry experiments indicate that PHGDH binds to PCBP2, an RNA-binding protein, and inhibits its ubiquitination degradation. PCBP2 in turn stabilizes SLC7A11 mRNA and increases its expression. NCT-502, a PHGDH inhibitor, promotes ferroptosis and inhibits tumor progression in BCa. PHGDH+ SLC7A11 score was significantly correlated with patient prognosis.
Conclusions: In all, PHGDH via interaction with PCBP2, upregulates SLC7A11 expression. This inhibits ferroptosis and promotes malignant progression of BCA. We also preliminarily assessed that NCT-502 could serve as a therapeutic strategy for BCa

PHGDH inhibits ferroptosis and promotes malignant progression by upregulating SLC7A11 in bladder cancer