KDM4A promotes the growth of non-small cell lung cancer by mediating the expression of Myc via DLX5 through the Wnt/β-catenin signaling pathway

Lung Cancer

Life Sci. 2020 Sep 28:118508. doi: 10.1016/j.lfs.2020.118508. Online ahead of print.


AIMS: Lung cancer represents as the most prevalent tumor globally, among which non-small cell lung cancer (NSCLC) takes up for more than 80%. Lysine demethylase 4A (KDM4A) was dysregulated in NSCLC, but its role on the tumorigenesis in NSCLC cells and the mechanisms of actions are unclear. In this work, we evaluated its connection with NSCLC prognosis, cell proliferation, migration and invasion.

MATERIALS AND METHODS: The cancer tissues and adjacent tissues of NSCLC patients were collected, and differentially expressed genes were sequenced by transcriptome. Subsequently, cell growth, apoptosis and metastasis were detected after overexpression or knockdown of KDM4A in NSCLC cell lines. Subsequently, changes in distal-less homeobox 5 (DLX5) promoter histone methylation levels were further detected by ChIP-qPCR, and genes that might be regulated by DLX5 were predicted through the JASPAR website. Finally, the effects of DLX5, Myc and Wnt/β-catenin signaling on the growth, apoptosis and metastasis of NSCLC were investigated by functional rescue experiments.

KEY FINDINGS: KDM4A was significantly highly expressed in NSCLC patients and cell lines. Knockdown of KDM4A suppressed the growth and metastasis of NSCLC cell lines in vitro and in vivo, and promoted apoptosis. ChIP-qPCR results demonstrated that KDM4A increased DLX5 transcriptional activity by promoting the demethylation of DLX5. Moreover, DLX5 activated the expression of an oncogene Myc and the downstream Wnt/β-catenin signaling, thereby promoting the occurrence, metastasis and growth of NSCLC.

SIGNIFICANCE: Our studies indicated that KDM4A is involved in NSCLC progression via the DLX5/Myc/Wnt/β-catenin axis, which might serve as a potential prognostic marker.