Abstract
BackgroundCell division cycle associated 4 (CDCA4) has been reported to be engaged into the progression of several cancers. The function of CDCA4 in Non-small cell lung cancer (NSCLC) was unknown. We aimed to explore the critical role of CDCA4 in NSCLC.MethodsCDCA4 stably knocking down and overexpression cell lines were established and Western blotting assay was applied to measure relevant protein expression of Epithelial-Mesenchymal Transtion (EMT) and cell autophagy. Staining of acidic vacuoles, transmission electron microscopy and immunofluorescence staining were employed to detect autophagy. The ability of cells to migrate and invade were detected by Transwell migration and invasion assays. The interaction of CDCA4 with CARM1 was identified by immunoprecipitation and Western blotting analysis.ResultsIn the present study, it was found that inhibition of CDCA4 induced EMT, migration and invasion of NSCLC cells while inhibiting autophagy of NSCLC cells. Meanwhile, overexpression of CDCA4 in NSCLC cells showed the opposite function. More importantly, the inhibition of autophagy could promote the EMT, migration and invasion of NSCLC cells, which should be impaired via the activation of autophagy. In addition, CDCA4-inhibited EMT, migration and invasion could be partially aggravated by autophagy activator, rapamycin, and reversed by autophagy inhibitor, 3-MA. Correspondingly, the application of rapamycin or 3-MA to CDCA4 knockdown cells showed the opposite effects. Further investigation suggested that CDCA4 could interact with coactivator associated arginine methyltransferase 1 (CARM1). Autophagy was induced while cell migration and invasion were inhibited in CARM1 knockdown cells. CDCA4 could suppress the protein expression CARM1 and knocking down of CARM1 could alter cell autophagy, migratory and invasive abilities regulated by CDCA4.ConclusionAll data indicated that CDCA4 inhibited the EMT, migration and invasion of NSCLC via interacting with CARM1 to modulate autophagy.
Highlights
Cell division cycle associated 4 (CDCA4) has been reported to be engaged into the progression of several cancers
CDCA4 suppresses Epithelial-Mesenchymal Transtion (EMT), migration and invasion in Non-small cell lung cancer (NSCLC) cells According to the relative expression quantity of CDCA4 on both mRNA and protein level (Fig. 1a, b), H1299 and A549 cell lines were selected to perform subsequent experiments as the abundance of CDCA4 was high in H1299 and medium in A549
As CDCA4 has previously been shown to serve as an autophagy regulator, we propose a hypothesis that autophagy played a crucial role in the process of CDCA4 regulating EMT, migration and invasion of NSCLC cells
Summary
Cell division cycle associated 4 (CDCA4) has been reported to be engaged into the progression of several cancers. The function of CDCA4 in Non-small cell lung cancer (NSCLC) was unknown. Previous studies had indicated that some members of this gene family might have potential diagnostic and porgnostic values for both ovarian cancer [5] and hepatocellular carcinoma [6]. Its role as cancer promoter was reported in hepatocellular carcinoma [8]. CDCA4 worked as a tumor suppressor gene in cervical cancer as the knockdown of CDCA4 could promote cell proliferation [9]. Our study aims at filling in the gap in understanding the contribution of CDCA4 to NSCLC progression, which may provide basic molecular target for developing new therapeutic strategies for NSCLC
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