Transcription factor TFAP2A upregulates CDC6 to mediate glycolysis and promote stemness in lung adenocarcinoma cells

Background: Lung adenocarcinoma (LUAD) is a kind of lung Cancer characterized by Cancer stem cell (CSC) properties. Cell division cycle 6 (CDC6), a cell cycle regulator, is significantly associated with tumor progression, but its role in LUAD stemness remains unclear.

Methods: CDC6 expression levels were analyzed using RNA-seq data from the TCGA database and clinical samples. Cell sphere formation assays, immunofluorescence, and western blot were performed to evaluate the impact of CDC6 on LUAD stemness. Lactate production and the extracellular acidification rate (ECAR) were measured to assess glycolysis levels. The hTFtarget database was used to screen potential upstream regulators, and the regulatory relationship between transcription factor AP-2α (TFAP2A) and CDC6 was validated by luciferase reporter assays and ChIP-qPCR. A xenograft tumor model was established to examine the result of CDC6 knockdown on LUAD tumor progression.

Results: The results indicated that CDC6 expression was markedly elevated in LUAD tissues compared with adjacent normal tissues, and high CDC6 expression was associated with poorer overall survival. In vitro experiments confirmed that CDC6 enhanced LUAD stemness by activating glycolysis. Mechanistic studies revealed that TFAP2A directly bound to the CDC6 promoter region, regulating its transcription and expression, thereby promoting glycolysis and LUAD stemness. In vivo experiments further demonstrated that knockdown of CDC6 in LUAD cells suppressed tumor growth.

Conclusion: This study clarifies the molecular mechanism through which TFAP2A modulates CDC6-mediated glycolysis to enhance LUAD stemness, implying that targeting the TFAP2A/CDC6 axis could serve as a potential therapeutic approach for LUAD.