GALE-dependent glycoproteome remodelling is a determinant of oncogenic RAS transformation

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Abstract Oncogenic transformation is accompanied by extensive remodelling of the cellular glycosylation landscape, yet the mechanisms linking oncogenic signalling to glycoproteome reprogramming remain poorly defined. We used site-resolved intact glycoproteomics to systematically map oncogenic RAS-dependent changes across the N- and O-linked glycoproteome. Integrating multiomics profiling with functional approaches, we identify UDP-glucose 4-epimerase (GALE) as a transcriptional target of oncogenic RAS that is induced through MAPK signalling and MYC-dependent transcription. GALE depletion selectively disrupted RAS-dependent glycoproteome remodelling, preferentially impairing sialylation of N-linked glycans and O-linked GalNAc-type glycosylation. Functionally, these glycosylation defects were accompanied by suppressed anchorage-independent growth and reduced in vivo tumorigenicity of KRAS -mutant cells, establishing GALE-dependent nucleotide-sugar interconversion as a requirement for malignant growth. Clinically, GALE expression was elevated in pancreatic ductal adenocarcinoma, wherein KRAS mutations are highly prevalent, and across a broad spectrum of human cancers. Collectively, our findings define a regulatory axis that connects oncogenic signalling to nucleotide-sugar precursor availability and diversification of the cellular glycan repertoire, revealing GALE as a metabolic dependency in RAS-driven cancer.

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