TMET-10. TARGETING PGM3 TO INHIBIT HEXOSAMINE PRODUCTION IS AN EFFECTIVE APPROACH TO TREAT GLIOBLASTOMA

Abstract Hexosamine biosynthesis pathway (HBP) mediated by a series of enzymes is highly upregulated in many cancers to promote the glycosylation of proteins and lipids, while which enzyme in this pathway is better to serve as anti-tumor target is unclear. Here, we found targeting GFAT1, the initial and rate-limiting enzyme in HBP, fails to inhibit the growth of glioblastoma (GBM), the most lethal brain tumor, due to this cancer dramatically elevating NAGK-mediated hexosamine salvage pathway. In contrast, targeting PGM3, the latter enzyme in HBP, blocks both de novo hexosamine synthesis and salvage pathways, effectively inhibiting GBM growth. We further identified HBP enzymes are upregulated by SREBP-1, a key lipogenic transcriptional factor. In turn, this upregulation promotes SREBP-1 activation to stimulate lipogenesis via stabilization of its key transporter SCAP by N-glycosylation modification. Together, our study uncovered a previously unrecognized HBP-SCAP-SREBP-1 feedforward loop and demonstrated targeting PGM3 is an effective approach to treat GBM.