Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/β-catenin pathway in hepatocellular carcinoma

Abstract

It has been reported that the transcription factor activating enhancer-binding protein 4 (TFAP4) is upregulated and associated with an aggressive phenotype in several cancers. However, the precise mechanisms underlying the oncogenic role of TFAP4 remain largely unknown. <b>Methods:</b> TFAP4 expression levels in hepatocellular carcinoma (HCC) cells and tissues were detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). <i>In vitro</i> and <i>in vivo</i> assays were performed to investigate the oncogenic function of TFAP4 in the tumor-initiating cell (TIC)-like phenotype and the tumorigenic capability of HCC cells. Luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays were performed to determine the underlying mechanism of TFAP4-mediated HCC aggressiveness. <b>Results:</b> TFAP4 was markedly upregulated in human HCC, and was associated with significantly poorer overall and relapse-free survival in patients with HCC. Furthermore, we found that overexpression of TFAP4 significantly enhanced, whereas silencing TFAP4 inhibited, the tumor sphere formation ability and proportion of side-population cells in HCC cells <i>in vitro</i>, and ectopic TFAP4 enhanced the tumorigenicity of HCC cells <i>in vivo</i>. Mechanistically, we demonstrated that TFAP4 played an important role in activating Wnt/β-catenin signaling by directly binding to the promoters of <i>DVL1</i> (dishevelled segment polarity protein 1) and <i>LEF1</i> (lymphoid enhancer binding factor 1). <b>Conclusions:</b> Our results provide new insight into the mechanisms underlying hyperactivation of the Wnt/β-catenin pathway in HCC, as well the oncogenic ability of TFAP4 to enhance the tumor-forming ability of HCC cells.