ZSCAN18 Promoter is Hypermethylated and Its Restored Expression Inhibits Proliferation in Gastric Cancer

Background: Zinc finger and scan domain containing 18 (ZSCAN18) belongs to the zinc finger transcription factor superfamily, which consists of hundreds of members that play critical roles in all steps of tumorigenesis. Although hypermethylation of the ZSCAN18 promoter and its consequent deficiency in a variety of malignancies have been reported recently, its functions and mechanisms in the initiation and progression of gastric cancer (GC) are not clear. This study aims to investigate the roles of ZSCAN18 in gastric carcinogenesis.Methods: Methylation of ZSCAN18 promoter in GC cell lines was analyzed via MassARRAY and treatment with 5-aza-2′-deoxycytidine. Bioinformatics analysis, quantitative real-time polymerase chain reaction (qRT-PCR), western blot, immunohistochemistry, Cell Counting Kit 8, colony formation, and an in vivo xenograft tumor model were used to examine the expression and function of ZSCAN18. Survival analysis was performed to determine the correlation between ZSCAN18 expression and the prognosis of patients with GC. Genes modulated by ZSCAN18 in NCI-N87 cells were identified through RNA next-generation sequencing and verified by qRT-PCR in AGS and NCI-N87 cells.Results: ZSCAN18 expression was markedly reduced in GC tissues compared with adjacent normal tissues as a result of hypermethylation in GC. Likewise, ZSCAN18 expression was significantly reduced in a panel of GC cell lines as a result of the densely methylated ZSCAN18 promoter. Forced expression of ZSCAN18 inhibited proliferation in AGS and NCI-N87 cells in vitro. Additionally, ZSCAN18 impaired the growth of NCI-N87 cells in immunodeficient mice. Survival analysis showed that ZSCAN18 expression was positively associated with favorable outcomes in patients with GC. RNA next-generation sequencing showed three representative genes (FGF20, CEACAM5, and TP53INP2) involved in downstream signaling pathways modulated by ZSCAN18.Conclusions: Collectively, this study unveils the anti-cancer role of ZSCAN18 in GC and provides a promising diagnostic and therapeutic target.