Abstract
PFK1 glycosylation promotes proliferation and tumor formation by altering cell metabolism.
Major finding: PFK1 glycosylation promotes proliferation and tumor formation by altering cell metabolism.
Mechanism: Suppression of PFK1 activity stimulates the pentose phosphate pathway in cancer cells.
Impact: Inhibition of PFK1 glycosylation may reduce tumor growth by resetting metabolic pathways.
Metabolic reprogramming in cancer cells is essential to maintain high growth rates and protect against oxidative stress. These adaptive changes are facilitated in part by oncogenic mutations but can also be rapidly induced by posttranslational modifications of key metabolic regulators. Yi and colleagues investigated whether protein glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc), which is elevated in many tumors and has been implicated in tumor growth and metastasis, contributes to cellular metabolism. Increased levels of O-GlcNAc, achieved via overexpression of O-GlcNAc transferase (OGT) or by inhibition of β-N-acetylglucosaminidase, reduced lactate and cellular ATP production. This decrease in glucose metabolism was mediated via suppression of phosphofructokinase 1 (PFK1), a critical regulatory glycolytic enzyme, in the presence of elevated O-GlcNAc. Glycosylated PFK1 was detected in multiple cancer cell lines and human tumor tissues but not in rapidly proliferating normal T cells or fibroblasts, indicating that this modification is specific to transformed cells, and this modification was enhanced by hypoxia. PFK1 was directly modified by O-GlcNAc at serine 529 within the binding pocket for fructose-2,6-bisphosphate, an allosteric activator of PFK1, and mutation of this conserved serine to alanine (S529A) rescued PFK1 activity from the inhibitory effects of O-GlcNAc. PFK1 glycosylation triggered a metabolic switch from glycolysis to increased flux through the oxidative pentose phosphate pathway, which allowed cancer cells to sustain production of biosynthetic precursors and NADPH. Furthermore, OGT expression promoted cell proliferation and increased tumor growth in mice; these effects were dependent on PFK1 glycosylation, as PFK1 depletion or expression of the S529A mutant PFK1 abrogated this growth advantage. Together, these findings demonstrate an important role for O-GlcNAc glycosylation in the regulation of cancer cell metabolism and suggest that blocking this modification may reverse these metabolic changes and constrain tumor growth.
