Fructose-1,6-bisphosphatase 1 suppresses PPARα-mediated gene transcription and non-small-cell lung cancer progression

Rongkai Shi; Jingjing Tao; Xiaoming Jiang; Min Li; Rongxuan Zhu; Shudi Luo; Zhimin Lu

Fructose-1,6-bisphosphatase 1 suppresses PPARα-mediated gene transcription and non-small-cell lung cancer progression

Am J Cancer Res. 2023 Oct 15;13(10):4742-4754. eCollection 2023.

Authors

Rongkai Shi^{1

2}, Jingjing Tao^{1

2}, Xiaoming Jiang^{1

2}, Min Li^{1

2}, Rongxuan Zhu^{1

2}, Shudi Luo^{1

2}, Zhimin Lu^{1

2}

Affiliations

¹ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine Hangzhou 310029, Zhejiang, China.
² Cancer Center, Zhejiang University Hangzhou 310029, Zhejiang, China.

PMID: 37970353
PMCID: PMC10636673

Abstract

Rapidly growing tumors often encounter energy stress, such as glutamine deficiency. However, how normal and tumor cells differentially respond to glutamine deficiency remains largely unclear. Here, we demonstrate that glutamine deprivation activates PERK, which phosphorylates FBP1 at S170 and induces nuclear accumulation of FBP1. Nuclear FBP1 inhibits PPARα-mediated β-oxidation gene transcription in normal lung epithelial cells. In contrast, highly expressed OGT in non-small cell lung cancer (NSCLC) cells promotes FBP1 O-GlcNAcylation, which abrogates FBP1 phosphorylation and enhances β-oxidation gene transcription to support cell proliferation under glutamine deficiency. In addition, FBP1 pS170 is negatively correlated with OGT expression in human NSCLC specimens, and low expression of FBP1 pS170 is associated with poor prognosis in NSCLC patients. These findings highlight the differential regulation of FBP1 in normal and NSCLC cells under glutamine deprivation and underscore the potential to target nuclear FBP1 for NSCLC treatment.

Keywords: FBP1; O-GlcNAcylation; glutamine deprivation; non-small cell lung cancer (NSCLC); phosphorylation; prognostic biomarker.