Abstract

Cancer cells reprogram the metabolic pathways to adapt to nutrient deficiency, while the underlying mechanism has not been fully understood. Phosphofructokinase 1 muscle type (PFKM) is the second rate-limiting step of glycolysis, catalyzing the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate. Here we show, using an orthotopic xenograft glioma mouse model, that PFKM is deubiquitinated and translocated into nucleus upon glucose deficiency, thereby activating fatty acid oxidation (FAO), which sustains tumor cell survival and ultimately promotes glioblastoma (GBM) development. Mechanistically, the levels of fructose-2,6-bisphosphate (F-2,6-BP) are decreased in tumor cells upon glucose deficiency, which enhances the interaction between ubiquitin carboxyl-terminal hydrolase 7 (USP7) and PFKM. USP7 removes the monoubiquitination of PFKM at lysine (K) 615, thereby promoting PFKM’s translocation into the nucleus. Nuclear PFKM interacts with c-MYC, which upregulates the expression of carnitine o-palmitoyltransferase 1 muscle isoform (CPT1B) to activate FAO, thereby sustaining tumor cell survival upon glucose deficiency. Notably, USP7 inhibitor effectively dampens GBM development and extends the survival duration of the mice. The levels of nuclear PFKM correlate with the malignancy and prognosis of human GBM patients. Our findings reveal a novel mechanism through which USP7 senses fructose-2,6-bisphosphate levels to promote PFKM nuclear translocation, thereby sustaining tumor cell survival under nutrient deficiency by activating FAO. This establishes the critical role of USP7 in brain tumor development and suggests the therapeutic potential of USP7 inhibitors for treating GBM.