USP7 facilitates brain tumor survival upon glucose deprivation by regulating phosphofructokinase muscle-type nuclear translocation in mice

TL;DR

This study reveals how brain tumors survive when glucose is scarce by switching to fat-burning, a process regulated by a protein called USP7.

Contribution

The study identifies a novel mechanism where USP7 regulates PFKM nuclear translocation to promote tumor survival under glucose deficiency.

Findings

PFKM translocates to the nucleus under glucose deficiency, activating fatty acid oxidation to sustain tumor cell survival.

USP7 deubiquitinates PFKM at K615, promoting its nuclear translocation and interaction with c-MYC to upregulate CPT1B.

USP7 inhibitors reduce glioblastoma development and improve survival in mice.

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.

We discover a novel function of PFKM in promoting glioma cell survival under glucose deficiency by switching metabolism from glycolysis to FAO. Upon GD, the levels of F-2,6-BP are decreased, leading to the enhanced interaction between USP7 and PFKM. USP7 then deubiquitinates PFKM K615 and promotes its nuclear translocation. Nuclear PFKM enhances c-Myc-dependent expression of CPT1B and the activity of FAO, and promotes tumor cell survival under GD.

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