LKB1 promotes lung adenocarcinoma cell senescence by suppressing the O-GlcNAc glycosylation-mediated activation of telomerase.

BACKGROUND

Telomeres are crucial for maintaining genomic integrity and stability, making them promising anticancer therapy targets. O-GlcNAc glycosylation is unique and involved in most cellular functions. In most cancers, there is a positive correlation between the degree of tumor malignancy and O-GlcNAc glycosylation levels. However, the relationship between O-GlcNAc glycosylation and telomerase in lung adenocarcinoma remains unclear. We thus investigated the O-GlcNAc-mediated regulation of telomerase activity.

METHODS

Protein and mRNA expression levels were detected via western blotting and RT-qPCR, respectively. Telomerase activity, telomere length, and telomere-induced injury foci were detected using telomeric repeat amplification protocol, telomere restriction fragment, and Q-FISH assays, respectively. Cell senescence and proliferation were detected using SA-β-gal staining and EdU assays. IHC and H&E staining were used to detect p53, PCNA, and BCL-2 protein levels in the transplanted tumor tissues and their effects on organs in transplanted tumor-bearing mice.

RESULTS

Our findings revealed that LKB1 reduces the overall activity of O-GlcNAcylation and telomerase, resulting in the shortening of telomeres, increased senescence and apoptosis, and decreased tumor cell growth. Insights into the underlying mechanisms have shown that LKB1-AMPK influence the hexosamine biosynthesis pathway (HBP), potentially via the phosphorylation of GFAT1. In vivo studies revealed that using both O-GlcNAc and telomerase inhibitors together led to the senescence of tumor cells and hindered their growth, suggesting a viable treatment method for clinical lung adenocarcinoma.

DISCUSSION: O-GlcNAc glycosylation promotes telomerase activity and inhibits tumor cell senescence, thereby maintaining telomere lengths in lung adenocarcinoma tumor cells. LKB1 inhibits telomerase activity via the HBP, which may depend on GFAT1 phosphorylation by LKB1. Telomerase inhibitors coupled with O-GlcNAc inhibitors significantly inhibit tumor growth in mice, suggesting clinical lung adenocarcinoma treatment strategies.