The Glycosyltransferase XYLT1 Activates NF-κB Signaling to Promote Metastasis of Early-Stage Lung Adenocarcinoma

Abstract Early-stage lung adenocarcinoma (LUAD) generally has a favorable prognosis. However, more than 30% of early-stage LUAD cases relapse within 5 years of initial treatment, even following complete removal of the primary tumor. Identification of the factors contributing to early-stage LUAD metastasis is needed to develop effective prevention and treatment strategies. Here, we found upregulation of xylosyltransferase 1 (XYLT1), a glycosyltransferase that initiates biosynthesis of sulfated glycosaminoglycan (sGAG) chains, in metastatic recurrent lesions of early-stage LUAD, which correlated with poor prognosis. In vitro and in vivo experiments showed that XYLT1 promoted LUAD cell survival and metastasis by activating the NF-κB pathway. Mechanistically, XYLT1 interacted with IκBα and facilitated biosynthesis of sGAG-conjugated IκBα, which enhanced the interaction between IκBα and IKKs to promote proteasomal degradation of IκBα. These results illustrate that proteoglycan modification-mediated activation of NF-κB signaling is a driver of early-stage LUAD metastasis, providing a possibility for detection and intervention of early LUAD metastasis.