Abstract:
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.
摘要:
尽管证实了LKB1在抑制肺癌进展中的作用,它对细胞衰老的确切影响是未知的。本研究旨在阐明LKB1在抑制肺腺癌端粒酶活性中的作用及机制。结果表明,LKB1在体外或体内均可诱导细胞衰老和凋亡。LKB1在LKB1缺陷型A549细胞中的过表达通过调节端粒酶逆转录酶(TERT)的表达而导致端粒酶活性的抑制和端粒功能障碍的诱导。作为转录因子,LKB1过表达后Sp1介导TERT抑制。LKB1诱导乳酸产生并抑制组蛋白H4(Lys8)和H4(Lys16)的乳酸化,这进一步改变了Sp1相关的转录活性。端粒酶抑制剂BIBR1532有助于实现传统化疗药物联合糖酵解抑制剂2DG的最佳疗效。这些数据揭示了LKB1通过依赖乳酸化的转录抑制调节端粒酶活性的新机制。因此,为LKB1介导的衰老在肺腺癌中的作用提供了新的见解。我们的研究为创造新的癌症治疗方法开辟了新的可能性。