Inactivation of ZSCAN18 by promoter hypermethylation drives the proliferation via attenuating TP53INP2-mediated autophagy in gastric cancer cells

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.

Methods: This study aims to investigate the roles of ZSCAN18 in gastric Cancer (GC). The expression level in GC and the clinicopathologic features of ZSCAN18 were detected by immunohistochemistry staining. Methylation of ZSCAN18 promoter in GC tissues and cell lines was analyzed via MassARRAY; the same method was used to detect GC cell lines demethylated by 5-aza-2'-deoxycytidine treatment. The biological function of ZSCAN18 in GC cells was verified by in vitro and in vivo experiments. The downstream molecular mechanism of ZSCAN18 was explored using RNA next-generation Sequencing, immunofluorescence and chromatin immunoprecipitation.

Results: Our work revealed 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. Functionally, ZSCAN18 overexpression inhibited the biological progression of GC cells, which was characterized by weaken proliferation, enhanced Autophagy and suppressed tumor growth. ZSCAN18 acted as a transcription factor and played an important role in binding to the promoter of tumor protein 53-induced nuclear protein 2 (TP53INP2), and we also confirmed the anti-tumor effect of TP53INP2 in GC. Furthermore, the knockdown of TP53INP2 alleviated the inhibiting effects of ZSCAN18 in GC cells by in vitro and in vivo experiments.

Conclusions: Collectively, this study unveiled that ZSCAN18 played an Anticancer role in GC by promoting Autophagy and transcriptional regulation of TP53INP2 and provided a promising target for the diagnosis and treatment of GC.

Autophagy; Carcinogenesis; Gastric cancer; Methylation; ZSCAN18.