C12orf59 Promotes Esophageal Squamous Cell Carcinoma Progression via YAP-Mediated Epithelial-Mesenchymal Transition

Abstract

C12orf59 is a novel gene widely expressed in diverse normal human tissues. Aberrant expression of C12orf59, which is involved in tumor progression, has been reported in a few types of cancer. However, its expression and biological function in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that the mRNA and protein levels of C12orf59 were prominently higher in both tumor tissues and most ESCC cell lines. Functionally, C12orf59 overexpression promoted ESCC cell proliferation, migration and invasion, whereas C12orf59 depletion worked oppositely. Mechanistically, C12orf59 exerted its oncogenic function through the induction of epithelial-mesenchymal transition (EMT) of ESCC cells, which relied on Yes-associated protein (YAP) dephosphorylation and nuclear translocation. Constitutively active YAP further facilitated cell migration, invasion and EMT induced by enforced C12orf59 overexpression. On the contrary, increased cell motility and EMT caused by enforced C12orf59 overexpression were dramatically repressed upon YAP inactivation by verteporfin. Thus, we conclude that YAP activation driven by C12orf59 contributes to the malignancy of ESCC through EMT and that targeting drugs for C12orf59 combined with YAP inhibitor may be a potential therapeutic strategy for ESCC.

Gene-Expression Patterns of Tumor and Peritumor Tissues of Smoking and Non-Smoking HPV-Negative Patients with Head and Neck Squamous Cell Carcinoma

“…Downstream targets of YAP (Yes-associated protein 1) are determined by its interactions with multiple transcriptional and epigenetic regulators whose expression and activity are dynamically modulated by oncogenic signaling. YAP acts as a transcription cofactor regulating the expression of genes involved in cell proliferation, EMT, and cell migration, all of which contribute to the pro-tumorigenic phenotype [ 20 , 71 , 72 ]. At the same time, it was shown that in different oral SSC cell lines, YAP can be overexpressed or, on the contrary, reduced due to phosphorylation and translocation from the cell nucleus to the cytoplasm [ 73 ].…”

The role of TMEM26 in disrupting tight junctions and activating NF-κB signaling to promote epithelial-mesenchymal transition in esophageal squamous cell carcinoma

“… 10 YAP activation driven by C12orf59, a novel cancer-related factor prominently higher in both tumor tissues and most ESCC cell lines, contributes to the EMT of ESCC, and thereby, combined treatment of C12orf59, and YAP inhibitors could be developed as a therapeutic strategy for metastatic ESCC. 11 Furthermore, a recent study revealed that neuron-specific gene family member 1 may amplify the ERK signaling pathway to promote ESCC cell EMT. 12 Hence, uncovering the molecules driving the EMT process can help identify therapeutic strategies and prolong the survival of patients with metastatic ESCC.…”