CircPTK2 enhances non-small cell lung cancer proliferation by inhibiting cellular senescence through stabilizing NFYA and elevating FOXM1.

[BACKGROUND AND PURPOSE] Cellular senescence, a stress-induced cell cycle arrest state, plays a dual role in cancer. Circular RNAs (circRNAs), endogenous noncoding RNAs, regulate physiological processes and are linked to diseases including cancer. This study investigates the role and mechanism of circPTK2 in non-small cell lung cancer (NSCLC).

[EXPERIMENTAL APPROACH] Lentivirus-mediated knockdown or overexpression of circPTK2 were used to assess effects on proliferation and senescence. circPTK2 expression in NSCLC tissues was examined using tissue microarrays and in situ hybridization. RNA-seq identified circPTK2-regulated signalling pathways and downstream targets. Transcriptional regulation of FOXM1 by NFYA was investigated using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. Co-immunoprecipitation (Co-IP) was conducted to assess the interaction between NFYA and MDM2, as well as NFYA ubiquitination.

[KEY RESULTS] circPTK2 was highly expressed in NSCLC tissues and was associated with poor prognosis. Knockdown of circPTK2 significantly inhibited cancer cell growth and enhanced cellular senescence. RNA-seq analysis identified FOXM1 as a downstream target of circPTK2. Database predictions suggested that NFYA could transcriptionally regulate FOXM1. Knockdown of circPTK2 induced NFYA degradation. circPTK2 was found to bind to the E3 ubiquitin ligase MDM2 in the cytoplasm, thereby preventing MDM2 from interacting with the transcription factor NFYA. This interaction blocked MDM2-mediated ubiquitylation and degradation of NFYA. Additionally, NFYA bound to the FOXM1 gene promoter, ultimately leading to the up-regulation of FOXM1 and suppression of cellular senescence.

[CONCLUSIONS AND IMPLICATIONS] Elevated circPTK2 expression correlates with poorer survival, representing a potential therapeutic target in NSCLC.