Hyaluronidase Promotes Glucose Metabolism: Identification of the Extracellular Matrix as a Node of Cell-Extrinsic Metabolic Regulation
- Author(s): Sullivan, William Juster
- Advisor(s): Christofk, Heather R.
- et al.
The metabolic state of a cell can be determined by cell-extrinsic factors, including nutrient availability and growth factor signaling. Here, we define extracellular matrix (ECM) remodeling as another fundamental node of cell-extrinsic metabolic regulation. Unbiased analysis of glycolytic drivers identified the hyaluronan-mediated motility receptor as among the most highly correlated with glycolysis in cancer. Confirming a mechanistic link between the ECM glycosaminoglycan hyaluronan and metabolism, treatment of cells with hyaluronidase (HAase) triggers a robust increase in glycolysis. This is largely achieved through rapid receptor tyrosine kinase-mediated induction of mRNA decay factor ZFP36, which targets TXNIP transcripts for degradation. Since TXNIP promotes internalization of the glucose transporter GLUT1, its acute decline liberates GLUT1 to the plasma membrane. In fibroblasts, the rapid induction of glycolysis induced by HAase is necessary for a concomitant increase in migration. Both tumor cross-sections and early mammalian embryos exhibit a ZFP36- and TXNIP-mediated interconnection between extracellular matrix remodeling and metabolism in vivo.
In a subset of cells, HAase has sustained metabolic effects that track with changes in cell identity. HAase treatment of LiSa-2 liposarcoma cells led to the identification of GLUT1 as a target of sialylation—the addition of a sialic acid residue as the terminal monosaccharide of its N-glycan linkage. Increases in this modification coincide with the transcriptional upregulation of various sialyltransferases. Consistent with previous reports that sialylation is upregulated as part of the epithelial-to-mesenchymal transition (EMT), the gene expression profile of HAase-treated cells closely resembles that of both EMT in breast cancer cells and the dedifferentiated state in melanoma. This change in the transcriptional state of the cell is accompanied by stable metabolic and epigenetic reprogramming.