Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
Department of Gastroenterology and Pancreatic Surgery, ShanXi Provincial People's Hospital, Taiyuan, 030000, People's Republic of China.
Clin Epigenetics. 2023 Jan 17;15(1):10. doi: 10.1186/s13148-023-01425-9.
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.
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.
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.
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.
锌指和扫描结构域包含 18 个（ZSCAN18）属于锌指转录因子超家族，该家族由数百个成员组成，在肿瘤发生的所有步骤中都发挥着关键作用。
本研究旨在探讨 ZSCAN18 在胃癌（GC）中的作用。通过免疫组织化学染色检测 GC 中 ZSCAN18 的表达水平和临床病理特征。通过 MassARRAY 分析 GC 组织和细胞系中 ZSCAN18 启动子的甲基化；同样的方法用于检测经 5-氮杂-2'-脱氧胞苷处理去甲基化的 GC 细胞系。通过体外和体内实验验证 ZSCAN18 在 GC 细胞中的生物学功能。使用 RNA 下一代测序、免疫荧光和染色质免疫沉淀探索 ZSCAN18 的下游分子机制。
我们的工作表明，与相邻正常组织相比，GC 组织中 ZSCAN18 的表达由于 GC 中的过度甲基化而明显降低。同样，由于 ZSCAN18 启动子的高度甲基化，在一系列 GC 细胞系中 ZSCAN18 的表达也显著降低。功能上，ZSCAN18 的过表达抑制了 GC 细胞的生物学进展，其特征是增殖减弱、自噬增强和肿瘤生长抑制。ZSCAN18 作为一种转录因子，在与肿瘤蛋白 53 诱导核蛋白 2（TP53INP2）的启动子结合方面发挥着重要作用，我们还证实了 TP53INP2 在 GC 中的抗肿瘤作用。此外，通过体外和体内实验，TP53INP2 的敲低减轻了 ZSCAN18 在 GC 细胞中的抑制作用。
综上所述，本研究揭示了 ZSCAN18 通过促进自噬和 TP53INP2 的转录调控在 GC 中发挥抗癌作用，并为 GC 的诊断和治疗提供了有前途的靶点。
