G9a Promotes Invasion and Metastasis of Non-Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-κB Signaling Pathway.
Ting SunKeqiang ZhangRajendra P PangeniJun WuWendong LiYong DuYuming GuoShyambabu ChaurasiyaLeonidas ArvanitisDan J RazPublished in: Molecular cancer research : MCR (2020)
Potential roles of euchromatic histone methyltransferase 2 (EHMT2 or G9a) in invasion and metastasis are not well understood in non-small cell lung cancer (NSCLC). Here, we investigated the effect and underlying mechanisms of G9a and therapeutic implications of targeting G9a in the invasion and metastasis of NSCLC. Overexpression of G9a significantly enhanced in vitro proliferation and invasion, while knockdown of G9a drastically suppressed in vivo growth and metastasis of A549 and H1299 NSCLC cells. Knockdown or inhibition of G9a significantly decreased the expression of focal adhesion kinase (FAK) protein and activation of FAK pathway. In addition, defactinib, a potent FAK inhibitor, partially abolished the G9a-enhanced invasion in these NSCLC cells. Furthermore, targeting G9a was found to suppress NF-κB transcriptional activity in NSCLC cells through stabilizing NF-κB inhibitor alpha (IκBα), while an NF-κB inhibitor Parthenilide partially abolished the G9a-enhanced FAK activation, which suggests that G9a-enhanced invasion and activation of FAK is mediated by elevated NF-κB activity. Notably, a strong positive correlation between the IHC staining of G9a and phosphorylated FAK proteins was identified in H1299 xenografts and 159 cases of NSCLC tissues (R = 0.408). IMPLICATIONS: The findings of this study strongly demonstrate that G9a may promote invasion and metastasis of NSCLC cells by enhancing FAK signaling pathway via elevating NF-κB transcriptional activity, indicating potential significance and therapeutic implications of these pathways in the invasion and metastasis of NSCLCs that overexpress G9a protein.
Keyphrases
- cell migration
- signaling pathway
- induced apoptosis
- pi k akt
- small cell lung cancer
- cell cycle arrest
- oxidative stress
- advanced non small cell lung cancer
- lps induced
- epithelial mesenchymal transition
- nuclear factor
- endoplasmic reticulum stress
- gene expression
- transcription factor
- poor prognosis
- tyrosine kinase
- dna methylation
- escherichia coli
- toll like receptor
- long non coding rna
- epidermal growth factor receptor
- binding protein
- climate change
- high resolution
- human health
- amino acid
- biofilm formation
- cancer therapy
- heat shock
- single molecule
- anti inflammatory
- atomic force microscopy