LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma

Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments. LKB1 induced cellular senescence through the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. Mechanistically, LKB1 reduces lactate production and inhibits histone H4 (Lys8) and H4 (Lys16) lactalytion, which further altered Sp1-related transcriptional activity especially TERT transcription. Telomere dysfunction activates DNA damage response and influences p53 related cellular senescence. However, p53 and p21 mediated G1 cell cycle arrest might provide an opportunity for telomerase-mediated telomere extension. Therefore, inhibiting telomerase activity and inducing LKB1-induced cellular senescence at the same time might be a valuable new treatment strategy to improve the outcome. [Display omitted]