IKZF4 acts as a novel tumor suppressor in non-small cell lung cancer by suppressing Notch signaling pathway.

Non-small cell lung cancer (NSCLC) is the predominant cause of cancer-related mortality globally, although many clinical efforts have been developed to improve the outcomes. The Ikaros zing-finger family transcription factors (IKZFs) have been proved to play pivotal roles in lymphopoiesis and myeloma progression, but their roles in solid tumors development remain unclear. We performed integrative bioinformatical analysis to determine the dysregulation expression of IKZFs in multiple tumors and the correlation between IKZF4 and NSCLC tumor environment. We showed that IKZFs were dysregulated in multiple tumors and IKZF4 was significantly decreased in NSCLC tissues and cell lines due to promoter hypermethylation. We found that low IKZF4 expression obviously correlated with patients' poor clinical outcome. We revealed that IKZF4 overexpression inhibited NSCLC cell growth, migration and xenograft tumor growth, supporting the inhibitory role of IKZF4 in NSCLC tumorigenesis. Additionally, integrative bioinformatical analysis showed that IKZF4 was involved in NSCLC tumor microenvironment. Mechanically, RNA-seq results showed that IKZF4 forced-expression remarkably suppressed Notch signaling pathway in NSCLC, which was validated by qRT-PCR and immunoblot assays. Moreover, we screened several potential agonists for IKZF4.