IL-17 induces non-small cell lung cancer metastasis via GCN5-dependent SOX4 acetylation enhancing MMP9 gene transcription and expression

Interleukin-17 (IL-17), a potent proinflammatory cytokine, can trigger the metastasis of non-small cell lung cancer (NSCLC). However, the underlying mechanism involved in IL-17-induced NSCLC cell metastasis remains unclear. In this study, we found that not only the expression of IL-17, IL-17RA, and/or general control nonrepressed protein 5 (GCN5), SRY-related HMG-BOX gene 4 (SOX4), and matrix metalloproteinase 9 (MMP9) was increased in the NSCLC tissues and in the IL-17-stimulated NSCLC cells, but also IL-17 treatment could enhance NSCLC cell migration and invasion. Further mechanism exploration revealed that IL-17-upregulated GCN5 and SOX4 could bind to the same region (-915 to -712 nt) of downstream MMP9 gene promoter driving its gene transcription. In the process, GCN5 could mediate SOX4 acetylation at lysine 118 (K118, a newly identified site) boosting MMP9 gene expression as well as cell migration and invasion. Moreover, the SOX4 acetylation or MMP9 induction and metastatic nodule number in the lung tissues of the BALB/c nude mice inoculated with the NSCLC cells stably infected by corresponding LV-shGCN5 or LV-shSOX4, LV-shMMP9 plus IL-17 incubation were markedly reduced. Overall, our findings implicate that NSCLC metastasis is closely associated with IL-17-GCN5-SOX4-MMP9 axis.

Automated summary

In this study, the researchers found that interleukin-17 (IL-17) is able to promote metastasis in non-small cell lung cancer (NSCLC). They also identified the potential mechanism behind IL-17-induced NSCLC cell metastasis. The results showed that IL-17, IL-17RA, GCN5, SOX4, and MMP9 were all increased in NSCLC tissues and IL-17-stimulated NSCLC cells, and IL-17 treatment enhanced cell migration and invasion. Further exploration revealed that IL-17-upregulated GCN5 and SOX4 could bind to the same region of the downstream MMP9 gene promoter, driving its transcription and promoting cell migration and invasion. By inhibiting the expression of GCN5, SOX4, or MMP9, the researchers observed reduced SOX4 acetylation, MMP9 induction, and metastatic nodule formation in NSCLC cells. Overall, this study suggests that the IL-17-GCN5-SOX4-MMP9 axis is closely associated with NSCLC metastasis.