AP4 activates cell migration and EMT mediated by p53 in MDA-MB-231 breast carcinoma cells

Abstract

Tumor metastasis is the primary cause of mortality in most cancer patients. Before disassociation from the tumors, most of malignant tumor cells undergo the epithelial-mesenchymal transition to break away from the adhesions between the cells and the surrounding extracellular matrix. Recently, activating enhancer-binding protein (AP4) has been shown to be a mediator of EMT in colorectal cancer and high level of AP4 correlates with poor prognosis in cancer patients. It has been found that AP4 upregulates the genes involved in EMT and cell proliferation in colorectal cancer cells and that the aggressive human breast cancer cells MDA-MB-231 are highly metastatic. Therefore, we tested the hypothesis that AP4 may also affect cell migration and EMT in this cell type. Three different assays, including the wound-healing assay, the Boyden chamber assay, and the cell tracking assay, were employed to confirm that AP4 activated both cell migration and invasion. Immunofluorescence staining and Western blot analysis revealed that the cells underwent EMT when AP4 was upregulated. In contrast, overexpression of dominant-negative AP4, lacking the DNA-binding domain, inactivated the DNA-binding ability of endogenous AP4 and led to lower cell motility. Furthermore, we found that AP4 enhanced p53 expression at both transcriptional and translational levels. Knockdown of p53 by siRNA significantly diminished the activation of cell migration by AP4, indicating that AP4 can regulate cell migration via the activity of p53.

The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating LAPTM4B Expression

“…Similar to our results, AP4 has been reported to promote cell growth in HCC [41], colorectal carcinoma [42] and gastric cancer [43]. Moreover, it has been proposed that AP4 could activate cell migration and EMT mediated by p53 in MDA-MB-231 cells [44] and mediate a c-MYC-induced EMT in colorectal cancer [45].…”

The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer

“…Interestingly, several genes that were downregulated such as ST3GAL 6 ( 55 ), FOXM1 ( 56 ) and AP4 ( 57 ) play a key role in breast cancer tumorigenesis and this interested us to probe more carefully how this regulation was orchestrated by the PRMT5/ WDR77 complex.…”

Ectopic AP4 expression induces cellular senescence via activation of p53 in long-term confluent retinal pigment epithelial cells

“…Recently they showed that AP4 stimulates the epithelial-mesenchymal transition in colorectal cancer [19], and AP4 suppresses cellular senescence by directly repressing p16 and p21 expression in AP4-deficient mouse embryo fibroblasts (MEFs) [20]. Our study previously demonstrated that AP4 can regulate cell migration via the activity of p53 in breast cancer cells [21]. We also shown that transcription factor AP4 in Drosophila controls tracheal terminal branching and cell growth [22].…”

“…Besides, several studies have shown that AP4 is expressed at elevated levels in several types of cancer, including pancreatic cancer [23], colorectal cancer [14], and gastric cancer [24]. High expression of AP4 correlated with poor patient survival and metastasis in cancers [21,24]. However, the cellular functions of high AP4 level in noncancerous cells are rarely reported.…”