Characterization of TCF4-mediated oncogenic role in cutaneous squamous cell carcinoma

The aberrant highly expressed T-cell factor 4 (TCF4) has been determined to be closely connected with carcinogenesis of cutaneous squamous cell carcinoma (cSCC) in previous studies. However, the underlying regulatory network and the potential therapeutic targets of TCF4 in SCC are still not fully understood. In this study, the highly expressed TCF4 was observed in human cSCC cancer compared to the paired adjacent tissues. A431 cell lines with TCF4 RNA silencing were found to be the repressive cell proliferation and invasion as well as the enhanced apoptosis. Furthermore, RNA-Seq was conducted and observed that 147 genes were up-regulated (including 113 coding genes and 34 lncRNA) while 172 genes were down-regulated (including 64 coding genes and 108 lncRNA) in TCF4 silencing compared to blank RNAi and untreated control A431 cells. 18 pathways including steroid, porphyrin, arachidonic acid, and retinol metabolism, as well as the functions associated with angiogenesis, inflammatory response, and cell adhesion were involved in the differentially expressed genes of A431 cells with TCF4 silencing. Finally, ChIP-qPCR of TCF4 and β-catenin were performed and we found that the enrichments of β-catenin were lost on the promoters on top ten down-regulated genes in A431 cells with TCF4 silencing compared to the untreated A431. Additionally, in untreated A431 cells, some genes such as ALDH8A1, DRICH1, and UGT1A5 were observed with high enrichment of TCF4, but without β-catenin, which indicated a Wnt/β-catenin independent way of TCF4 for gene transcriptional regulation. In conclusion, we declared that TCF4 played an important role in tumorigenesis of skin cancer via the aberrant activation of variety of signaling pathways, and could be considered as a potential therapeutic target for cSCC treatment.