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

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