Elevated Nuclear PHGDH Synergistically Functions with cMyc to Reshape the Immune Microenvironment of Liver Cancer.
Adv Sci (Weinh)
; 10(17): e2205818, 2023 06.
Article
en En
| MEDLINE
| ID: mdl-37078828
ABSTRACT
Herein, we observed that nuclear localization of phosphoglycerate dehydrogenase (PHGDH) is associated with poor prognosis in liver cancer, and Phgdh is required for liver cancer progression in a mouse model. Unexpectedly, impairment of Phgdh enzyme activity exerts a slight effect in a liver cancer model. In liver cancer cells, the aspartate kinase-chorismate mutase-tyrA prephenate dehydrogenase (ACT) domain of PHGDH binds nuclear cMyc to form a transactivation axis, PHGDH/p300/cMyc/AF9, which drives chemokine CXCL1 and IL8 gene expression. Then, CXCL1 and IL8 promote neutrophil recruitment and enhance tumor-associated macrophage (TAM) filtration in the liver, thereby advancing liver cancer. Forced cytosolic localization of PHGDH or destruction of the PHGDH/cMyc interaction abolishes the oncogenic function of nuclear PHGDH. Depletion of neutrophils by neutralizing antibodies greatly hampers TAM filtration. These findings reveal a nonmetabolic role of PHGDH with altered cellular localization and suggest a promising drug target for liver cancer therapy by targeting the nonmetabolic region of PHGDH.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fosfoglicerato-Deshidrogenasa
/
Neoplasias Hepáticas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Adv Sci (Weinh)
Año:
2023
Tipo del documento:
Article
País de afiliación:
China