Journal
NATURE CELL BIOLOGY
Volume 24, Issue 11, Pages 1655-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41556-022-01009-4
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Funding
- Ministry of Science and Technology of the People's Republic of China [2021YFA0805600, 2020YFA0803300]
- National Natural Science Foundation of China [92157113, 82072630, 82173114, 82188102, 82030074]
- Zhejiang Natural Science Foundation Discovery Project [LQ22H160023]
- Zhejiang Natural Science Foundation Key Project [LD22H160002, LD21H160003]
- Zhejiang University Research Fund [188020*194221901/029]
- Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang [2019R01001]
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Tumour cells exhibit greater metabolic plasticity than normal cells, but the mechanisms behind their selective advantages for survival and proliferation are not fully understood. This study found that glucose deprivation in normal hepatocytes induces PERK-mediated FBP1 S170 phosphorylation, leading to nuclear translocation and suppression of PPAR alpha-mediated beta-oxidation gene expression. In contrast, hepatocellular carcinoma cells exhibit O-GlcNAcylation of FBP1 S124, which inhibits FBP1 S170 phosphorylation and enhances beta-oxidation for tumour growth.
Tumour cells exhibit greater metabolic plasticity than normal cells and possess selective advantages for survival and proliferation with unclearly defined mechanisms. Here we demonstrate that glucose deprivation in normal hepatocytes induces PERK-mediated fructose-1,6-bisphosphatase 1 (FBP1) S170 phosphorylation, which converts the FBP1 tetramer to monomers and exposes its nuclear localization signal for nuclear translocation. Importantly, nuclear FBP1 binds PPAR alpha and functions as a protein phosphatase that dephosphorylates histone H3T11 and suppresses PPAR alpha-mediated beta-oxidation gene expression. In contrast, FBP1 S124 is O-GlcNAcylated by overexpressed O-linked N-acetylglucosamine transferase in hepatocellular carcinoma cells, leading to inhibition of FBP1 S170 phosphorylation and enhancement of beta-oxidation for tumour growth. In addition, FBP1 S170 phosphorylation inversely correlates with beta-oxidation gene expression in hepatocellular carcinoma specimens and patient survival duration. These findings highlight the differential role of FBP1 in gene regulation in normal and tumour cells through direct chromatin modulation and underscore the inactivation of its protein phosphatase function in tumour growth.
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