Cholesterol biosynthesis and mutant IDH activity are linked to cellular glycogen through PPP1R3C in growth plate chondrocytes and chondrosarcoma

Enchondromas are common bone tumors composed of chondrocytes originating from growth plate cells, which can progress to malignant chondrosarcoma. Mutations in the genes encoding isocitrate dehydrogenase (IDH1 and IDH2) are identified in a large proportion of these tumors. IDH enzymes convert isocitrate to alpha-ketoglutarate (α-KG), an essential component of the citric acid cycle. The mutant IDH enzymes produce 2-hydroxyglutarate (2-HG), which has epigenetic effects important in tumor initiation. Tumor maintenance and growth rely on additional factors as well. Prior work shows that intracellular cholesterol and glycogen are upregulated in mutant IDH chondrocytes. Here, we show that Protein Phosphatase 1 Regulatory Subunit 3C (PPP1R3C, previously termed Protein Targeting to Glycogen or PTG) is upregulated in chondrocytes harboring a mutant IDH. PPP1R3C expression correlates with the level of intracellular cholesterol biosynthesis and can be regulated by Sterol Regulatory Element-Binding Proteins (SREBPs), which are transcriptional regulators of enzymes involved in sterol biosynthesis. We found that PPP1R3C regulates glycolysis and glycolytic capacity in chondrocytes. Depletion of PPP1R3C in mouse chondrocytes in vivo suppresses the enchondroma phenotype. The growth plate phenotype associated with the inhibition of cholesterol biosynthesis is partially rescued by PPP1R3C overexpression. Taken together, our data show that PPP1R3C integrates the effects of cholesterol metabolism and isocitrate dehydrogenase on growth plate and neoplastic chondrocyte metabolism by regulating intracellular glycogen levels.