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

Abstract

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.

Enhancing the revelation of key genes and interaction networks in non‐small cell lung cancer with major depressive disorder: A bioinformatics analysis

“…The MMP9 has been extensively studied and its close association with proliferation, migration, and invasion has been well‐documented, primarily implicated in the metastasis of NSCLC. 77 , 78 , 79 In microvasculitis, the entry of monocytes and T cells into the blood vessel wall is elegantly regulated by MMP9. T cells rely on MMP9‐producing monocytes to gracefully traverse the basement membrane containing collagen‐IV.…”

Identification of anti-gastric cancer effects and molecular mechanisms of resveratrol: From network pharmacology and bioinformatics to experimental validation

“…In vitro experiments showed that the migration and invasion of cancer cells are mainly related to the up-regulation of the downstream gene MMP9, and in vivo experiments found that the number of metastatic nodules in lung tissues is significantly reduced after interfering with MMP9 expression. Specific mechanism exploration suggested that IL-17 regulation of non-small cell lung cancer metastasis is closely related to the GCN5-SOX4-MMP9 axis[ 46 ]. Metastasis is a major cause of cancer development and death, and the production of neutrophil extracellular traps (NETs) have an influential role in the pathogenesis of the metastatic cascade.…”