Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression.
A549 Cells
Animals
Breast Neoplasms
/ enzymology
Female
Humans
Lung Neoplasms
/ enzymology
MCF-7 Cells
Mice
Mice, Inbred BALB C
Mice, Knockout
Mice, Nude
Neoplasm Proteins
/ genetics
Phosphoglycerate Dehydrogenase
/ genetics
Proteolysis
Serine
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Ubiquitination
Metabolism
Oncology
Tumor suppressors
Ubiquitin-proteosome system
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
21
08
2019
accepted:
11
03
2020
entrez:
2
6
2020
pubmed:
2
6
2020
medline:
3
2
2021
Statut:
ppublish
Résumé
Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.
Identifiants
pubmed: 32478681
pii: 132876
doi: 10.1172/JCI132876
pmc: PMC7260041
doi:
pii:
Substances chimiques
Neoplasm Proteins
0
Serine
452VLY9402
Phosphoglycerate Dehydrogenase
EC 1.1.1.95
Ubiquitin-Protein Ligases
EC 2.3.2.27
parkin protein
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3253-3269Subventions
Organisme : NCI NIH HHS
ID : R01 CA214746
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA203965
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227912
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA072720
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163591
Pays : United States
Commentaires et corrections
Type : CommentIn
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