Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Abstract

Cancer cells need to meet the metabolic demands of rapid cell growth within a continually changing microenvironment. Genetic mechanisms for reprogramming cellular metabolism toward proliferative, pro-survival pathways are well-reported. However, post-translational mechanisms, which would enable more rapid, reversible adaptations of cellular metabolism in response to protein signaling or environmental sensing systems, are less well understood. Here we demonstrate that the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) is a key metabolic regulator of glucose metabolism. O-GlcNAc is dynamically induced at Ser529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibits PFK1 activity and redirects the flux of glucose from glycolysis through the pentose phosphate pathway (PPP), thereby conferring a selective growth advantage to cancer cells. Blocking glycosylation of PFK1 at Ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal an unexpected mechanism for the regulation of metabolic enzymes and pathways, and pinpoint a new therapeutic approach for combating cancer.

Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

“…Here, in the context of PDAC, we suggest that GlcNAcylation allows cells to promptly react to microenvironmental stress situations such as hypoxia through stabilization of factors yet to be determined and involved in resistance to hypoxia and in its associated metabolic pathways. Very recently, Yi et al showed that phosphofructokinase 1, a key enzyme of glycolysis flux, is O-GlcNAcylated and that this PTM responsible for its inactivation redirects glucose flux through pathways critically involved in tumor growth as PPP (27). Therefore, the crucial role of HBP activation to maintain cell viability under hypoxic conditions might involve regulation of mediators including glycolytic enzymes.…”

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

“…Furthermore, conditional deletion of OGT results in cellular senescence and apoptosis in numerous cell types, including T cells (25). Considering that abnormal O-GlcNAc levels, possibly stemming from alterations in metabolism (26)(27)(28)(29), may contribute to the pathology of several diseases, including cancer, diabetes, and neurodegeneration (29)(30)(31)(32)(33)(34)(35)(36), a greater understanding of O-GlcNAc biology in T cells could help to explain the impact of metabolic health on the function of the immune system.making the relevance to primary T cells unclear. Furthermore, only a selected few proteins were surveyed.…”

Engineering the Pattern of Protein Glycosylation Modulates the Thermostability of a GH11 Xylanase

“…Glycosylation plays a key role in the regulation of enzyme activity (19), where the covalent addition of glycans to the protein surface may modulate kinetic parameters and thermal stability (14). These effects demonstrate that glycosylation affects the protein energy landscape, and it has been suggested that protein stabilization by glycosylation may be due to an enthalpic effect resulting from interactions between the protein and the attached glycans (17,20,21).…”