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

Summary

XYLT1 is upregulated in metastatic recurrent early-stage lung adenocarcinoma and promotes metastasis by enabling sGAG conjugation of IκBα, enhancing its proteasomal degradation and activating NF-κB signaling. The study links proteoglycan modification to a canonical inflammatory pathway as a driver of metastasis, offering biomarker and therapeutic target opportunities.

Key Findings

• XYLT1 is upregulated in metastatic recurrent lesions of early-stage lung adenocarcinoma and associates with poor prognosis.
• XYLT1 activates NF-κB signaling by promoting sGAG-conjugated IκBα and its proteasomal degradation via enhanced IKK interaction.
• In vitro and in vivo models demonstrate that XYLT1 augments lung adenocarcinoma cell survival and metastasis.
• Proteoglycan modification-mediated NF-κB activation is identified as a driver of metastatic recurrence.

Clinical Implications

XYLT1 and sGAG-conjugated IκBα could serve as biomarkers for early metastatic risk stratification and as targets to disrupt NF-κB activation in adjuvant settings.

Limitations

• Preclinical models require prospective clinical validation to establish predictive utility
• Potential context specificity; tumor heterogeneity and off-target effects of pathway modulation were not addressed

Future Directions

Validate XYLT1/sGAG-IκBα as biomarkers in prospective cohorts; develop inhibitors targeting XYLT1 or the sGAG-IκBα-IKK axis; explore synergy with adjuvant therapies.