Affiliation:
1. CAS Key Laboratory of Receptor Research State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
2. Precise Genome Engineering Center School of Life Sciences Guangzhou University Guangzhou 510006 China
3. Institute of Neuroscience State Key Laboratory of Neuroscience CAS Center for Excellence in Brain Science and Intelligence Technology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Shanghai 200031 China
Abstract
AbstractHerein, 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.
Funder
National Natural Science Foundation of China
National Key Research and Development Program of China
Youth Innovation Promotion Association of the Chinese Academy of Sciences
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)
Cited by
2 articles.
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