Starvation-induced HBP metabolic reprogramming and STAM2 O-GlcNAcylation facilitate bladder cancer metastasis.

Metabolic reprogramming and epigenetic alternations are implicated in tumor progression and metastasis, but the metabolic and epigenetic mechanisms underlying lymphatic and distant metastasis of bladder cancer (BCa) remain poorly understood. In this study, we provide the first evidence that glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the crucial rate-limiting switch of the hexosamine biosynthesis pathway (HBP), is considerably upregulated in the nutrient-scarce microenvironment and causes a high O-GlcNAcylation of signal transducing adaptor molecule 2 (STAM2), further facilitating lymphatic and distant metastasis of BCa. Inhibition of GFAT1 and O-GlcNAcylation impairs STAM2-induced metastasis. Mechanistically, O-GlcNAcylation of STAM2 at serine 375 augments protein stability by inhibiting proteasome degradation and ubiquitination. In addition, STAM2 O-GlcNAcylation facilitates Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT3) phosphorylation, thus activating the epithelial‒mesenchymal transition. In summary, these results reveal a novel metabolic and epigenetic link mediating tumor metastasis, and indicate that targeting GFAT1 and STAM2 O-GlcNAcylation may serve as a promising treatment strategy for BCa progression.