Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARalpha-regulated gene transcription and tumour growth
Menée in vitro et à l'aide d'un modèle murin, cette étude démontre que la privation de glucose favorise l'accumulation de la fructose-1,6-bisphosphatase 1 dans le noyau des hépatocytes normaux et que l'inactivation de cette enzyme (par la O-GlcNAc-glycosylation de la sérine 124) dans les cellules hépatiques cancéreuses favorise l'activité du récepteur PPAR alpha, la bêta-oxydation et la croissance tumorale
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
α and functions as a protein phosphatase that dephosphorylates histone H3T11 and suppresses PPARα-mediated β-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 β-oxidation for tumour growth. In addition, FBP1 S170 phosphorylation inversely correlates with β-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.
Nature Cell Biology 2022