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

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. ©2025 American Association for Cancer Research.

Citation

Jian Han, Jianan Du, Xiangmeng Li, Qingbo Zhou, Jiayu Zeng, Jun-Tao Lin, Wenle Zhou, Jiayi Cai, Yaokai Ye, Bosui Yang, Junsheng Wang, Xiang Zhou, Rong Lian, Yi Yang, Xun Zhu, Hongyu Guan, Liping Liu, Junchao Cai, Jueheng Wu, Yun Li, Mengfeng Li, Han Tian. The Glycosyltransferase XYLT1 Activates NF-κB Signaling to Promote Metastasis of Early-Stage Lung Adenocarcinoma. Cancer research. 2025 May 02;85(9):1628-1643

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PMID: 39992715

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