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PHGDH Drives 5-FU Chemoresistance in Colorectal Cancer through the Hedgehog signaling

ABSTRACT: This study investigates the role of phosphoglycerate dehydrogenase (PHGDH) in 5-fluorouracil (5-FU) chemoresistance in colorectal cancer (CRC). The researchers discovered that PHGDH expression is highly variable in tumor tissues and patient-derived CRC organoids, with elevated PHGDH levels correlating with reduced sensitivity to 5-FU treatment. Through transcriptomic analysis, PHGDH was found to promote activation of the Hedgehog (HH) signaling pathway, which plays a key role in chemoresistance. PHGDH silencing reduces HH activation and increases sensitivity to 5-FU, while PHGDH overexpression has the opposite effect. Significantly, combined treatment with 5-FU and HH pathway inhibitors (JC19 or GANT61) synergistically enhances chemosensitivity in high-PHGDH expressing CRC cells, organoids, and xenograft models. This dual-targeting approach effectively limits tumor growth in mice. The findings establish PHGDH as a potential biomarker for predicting response to 5-FU-based chemotherapy and suggest that targeting the PHGDH-HH axis may represent a promising therapeutic strategy to overcome chemoresistance in CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294639 | GEO | 2025/07/11

REPOSITORIES: GEO

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Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Experiment Overall Design: Total RNA samples were prepared from head tissues from 2 embryos of Phgdh knockout and littermate wild-type controls. Experiment Overall Design: RNA of 4 biological replicates was hybridized to Affymetrix Mouse Genome 430 2.0 arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

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PHGDH Drives 5-FU Chemoresistance in Colorectal Cancer through the Hedgehog signaling

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