Dataset Information

O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia.

ABSTRACT: The protein O-GlcNAcylation catalysed by O-GlcNAc transferase (OGT) is tightly regulated by glucose availability. It is upregulated and essential for tumor cell proliferation under hypoxic conditions. However, the mechanism behind is still unclear. Here, we showed that the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), which also promotes cell cycle progression in the nucleus, was O-GlcNAcylated in response to hypoxia. The O-GlcNAcylation of PFKFB3 could compete phosphorylation by hypoxia-activated ERK at the same modification site Ser172. Phosphorylated PFKFB3 could interact with the protein G3BP2 and retain in the cytosol; this in turn led to the accumulation of hypoxia-induced-P27 in the nucleus resulting in the cell cycle arrest. Such a pathway was compromised by high level of PFKFB3 O-GlcNAcylation in tumor cells contributing to cell cycle progression. Consistently, the PFKFB3-Ser172 phosphorylation level inversely correlated with the OGT level in pancreatic cancer patients. Our findings uncovered an O-GlcNAcylation mediated mechanism to promote tumor cell proliferation under metabolic stress, linking the aberrant OGT activity to tumorigenesis in pancreatic cancer.

SUBMITTER: Lei Y

PROVIDER: S-EPMC7021673 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia.

Lei Yinrui Y Chen Tao T Li Yeyi Y Shang Man M Zhang Yan Y Jin Yuepeng Y Yu Qiujing Q Guo Fang F Wang Ting T

Oncogenesis 20200214 2

The protein O-GlcNAcylation catalysed by O-GlcNAc transferase (OGT) is tightly regulated by glucose availability. It is upregulated and essential for tumor cell proliferation under hypoxic conditions. However, the mechanism behind is still unclear. Here, we showed that the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), which also promotes cell cycle progression in the nucleus, was O-GlcNAcylated in response to hypoxia. The O-GlcNAcylation of PFKFB3 could comp ...[more]

PMID: 32060258

Similar Datasets

Project description:Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing ?-ketoglutarate (?KG). ?KG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.

Dataset Information

O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia.

Publications

O-GlcNAcylation of PFKFB3 is required for tumor cell proliferation under hypoxia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets