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

  • Cancer Res. 2025 Feb 24. doi: 10.1158/0008-5472.CAN-24-1893.
Jian Han  1 ,  Jianan Du  2 ,  Xiangmeng Li  3 ,  Qingbo Zhou  2 ,  Jiayu Zeng  2 ,  Jun-Tao Lin  4 ,  Wenle Zhou  2 ,  Jiayi Cai  2 ,  Yaokai Ye  2 ,  Bosui Yang  2 ,  Junsheng Wang  5 ,  Xiang Zhou  6 ,  Rong Lian  2 ,  Yi Yang  7 ,  Xun Zhu  7 ,  Hongyu Guan  8 ,  Liping Liu  9 ,  Junchao Cai  10 ,  Jueheng Wu  10 ,  Yun Li  5 ,  Mengfeng Li  11 ,  Han Tian  12
Affiliations
  • 1. Southern Medical University, Guangzhou, China.
  • 2. Sun Yat-sen University, China.
  • 3. Southern Medical University, China.
  • 4. Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 5. Jinan University, China.
  • 6. Trauma and Hand Surgery, the First Affiliated Hospital of Sun Yat-sen University, China.
  • 7. Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 8. First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 9. First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 10. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 11. Southern Medical University, Guangzhou, Guangdong, China.
  • 12. Sun Yat-sen University, Guangzhou, China.
PMID: 39992715 DOI: 10.1158/0008-5472.CAN-24-1893
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.

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