Transcriptomic analysis by RNA-seq reveals AP-1 pathway as key regulator that green tea may rely on to inhibit lung...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Green tea polyphenols show potential in lung cancer chemoprevention.
• The precise mechanisms underlying green tea's chemopreventive effects are not fully understood.
• The role of Activator Protein-1 (AP-1) in mediating these effects requires further investigation.

Purpose of the Study:

• To investigate the involvement of AP-1 in the tumor-inhibitory effects of green tea polyphenols.
• To determine if AP-1 is a key mediator of green tea's chemopreventive activity against non-small cell lung cancer (NSCLC).

Main Methods:

• Utilized AP-1 dependent NSCLC cell lines (H1299) and mouse cells (SPON 10) with inducible TAM67 expression.
• Employed RNA-sequencing (RNA-seq) to analyze global gene expression changes upon AP-1 inhibition and Polyphenon E treatment.
• Conducted ChIP-seq analysis to identify direct AP-1 binding sites in down-regulated genes.
• Validated findings using conditional TAM67 expressing transgenic mice and NSCLC cell lines.

Main Results:

• AP-1 activity was confirmed as crucial for cell growth inhibition in H1299 and SPON 10 cells.
• RNA-seq revealed significant overlap in down-regulated genes between AP-1 inhibition and Polyphenon E treatment.
• Over 10% of Polyphenon E-down-regulated genes contained direct AP-1 binding sites, suggesting AP-1 regulation.
• Polyphenon E's chemopreventive efficacy was abolished both in vitro and in vivo when AP-1 was inhibited.

Conclusions:

• Green tea's chemopreventive activity against lung cancer is significantly mediated through the regulation of AP-1 target genes.
• Inhibition of AP-1 is a major pathway through which green tea polyphenols exert their anti-cancer effects.