浙江大学Zhimin Lu和Daqian Xu团队合作的研究发现，果糖-1,6-二磷酸酶1（FBP1）可作为蛋白磷酸酶介导组蛋白H3去磷酸化抑制PPARα-调节基因的转录和肿瘤生长。2022年10月20日，国际学术期刊《自然-细胞生物学》发表了这一成果。

研究人员证明剥夺正常肝细胞中的葡萄糖会诱导PERK介导的FBP1 S170位的磷酸化，其将FBP1四聚体转化为单体并导致其核定位信号暴露以进行核易位。重要的是，核FBP1结合PPARα作为蛋白质磷酸酶起作用，其介导组蛋白H3 T11位的去磷酸化并抑制PPARα介导的β氧化基因表达。相反，在肝癌细胞中FBP1 S124会发生O-乙酰葡糖胺修饰，这是由于肝癌细胞过表达N-乙酰葡糖胺转移酶造成，这会抑制FBP1 S170的磷酸化并通过增强β氧化促进肿瘤细胞生长。

此外，FBP1 S170磷酸化与肝癌标本中的β氧化基因表达和患者生存时间呈负相关。这些发现表明FBP1在染色质水平调节正常细胞和肿瘤细胞的基因功能差异，并发现其蛋白质磷酸酶功能在肿瘤生长过程中失活。

据介绍，肿瘤细胞具有比正常细胞更强的代谢可塑性，并且具有生存和增殖的选择性优势，但机制不明。

附：英文原文

Title: Fructose-1,6-bisphosphatase 1 functions as a protein phosphatase to dephosphorylate histone H3 and suppresses PPARα-regulated gene transcription and tumour growth

Author: Wang, Zheng, Li, Min, Jiang, Hongfei, Luo, Shudi, Shao, Fei, Xia, Yan, Yang, Mengke, Ren, Xiangle, Liu, Tong, Yan, Meisi, Qian, Xu, He, Haiyan, Guo, Dong, Duan, Yuran, Wu, Ke, Wang, Lei, Ji, Guimei, Shen, Yuli, Li, Lin, Zheng, Peixiang, Dong, Bofei, Fang, Jing, Zheng, Min, Liang, Tingbo, Li, Haitao, Yu, Rilei, Xu, Daqian, Lu, Zhimin

Issue&Volume: 2022-10-20

Abstract: 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 PPARα 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.

DOI: 10.1038/s41556-022-01009-4

Source: https://www.nature.com/articles/s41556-022-01009-4