锌指和 SCAN 结构域蛋白 18 是乳腺癌中潜在的 DNA 甲基化修饰的肿瘤抑制因子和生物标志物。

Zinc finger and SCAN domain-containing protein 18 is a potential DNA methylation-modified tumor suppressor and biomarker in breast cancer.

机构信息

Health Management Department, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Academician (Expert) Workstation of Sichuan Province, Luzhou, China.

出版信息

Front Endocrinol (Lausanne). 2023 May 8;14:1095604. doi: 10.3389/fendo.2023.1095604. eCollection 2023.

DOI:10.3389/fendo.2023.1095604

PMID:37223020

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10200902/

Abstract

INTRODUCTION

Zinc finger and SCAN domain-containing protein 18 (ZSCAN18) has been investigated as a putative biomarker of multiple human cancers. However, the expression profile, epigenetic modification, prognostic value, transcription regulation, and molecular mechanism of ZSCAN18 in breast cancer (BC) remain unknown.

METHODS

In the study, we present an integrated analysis of ZSCAN18 in BC based on public omics datasets with the use of multiple bioinformatics tools. Genes potentially regulated through restoration of ZSCAN18 expression in MDA-MB-231 cells were investigated to identify pathways associated with BC.

RESULTS

We observed that ZSCAN18 was downregulated in BC and mRNA expression was significantly correlated with clinicopathological parameters. Low expression of ZSCAN18 was found in the HER2-positive and TNBC subtypes. High expression of ZSCAN18 was associated with good prognosis. As compared to normal tissues, the extent of ZSCAN18 DNA methylation was greater with fewer genetic alterations in BC tissues. ZSCAN18 was identified as a transcription factor that might be involved in intracellular molecular and metabolic processes. Low ZSCAN18 expression was associated with the cell cycle and glycolysis signaling pathway. Overexpression of ZSCAN18 inhibited mRNA expression of genes associated with the Wnt/β-catenin and glycolysis signaling pathways, including CTNNB1, BCL9, TSC1, and PFKP. ZSCAN18 expression was negatively correlated with infiltrating B cells and dendritic cells (DCs), as determined by the TIMER web server and reference to the TISIDB. ZSCAN18 DNA methylation was positively correlated with activated B cells, activated CD8+ and CD4+ T cells, macrophages, neutrophils, and activated DCs. Moreover, five ZSCAN18-related hub genes (KDM6B, KAT6A, KMT2D, KDM1A, and HSPBP1) were identified. ZSCAN18, ZNF396, and PGBD1 were identified as components of a physical complex.

CONCLUSION

ZSCAN18 is a potential tumor suppressor in BC, as expression is modified by DNA methylation and associated with patient survival. In addition, ZSCAN18 plays important roles in transcription regulation, the glycolysis signaling pathway, and the tumor immune microenvironment.

摘要

简介

锌指和 SCAN 结构域蛋白 18（ZSCAN18）已被研究为多种人类癌症的潜在生物标志物。然而，ZSCAN18 在乳腺癌（BC）中的表达谱、表观遗传修饰、预后价值、转录调控和分子机制仍不清楚。

方法

在本研究中，我们基于公共组学数据集，使用多种生物信息学工具，对 ZSCAN18 在 BC 中的情况进行了综合分析。通过在 MDA-MB-231 细胞中恢复 ZSCAN18 表达来研究潜在受其调控的基因，以鉴定与 BC 相关的途径。

结果

我们观察到 ZSCAN18 在 BC 中下调，mRNA 表达与临床病理参数显著相关。ZSCAN18 在 HER2 阳性和三阴性乳腺癌（TNBC）亚型中的表达较低。ZSCAN18 高表达与预后良好相关。与正常组织相比，BC 组织中 ZSCAN18 的 DNA 甲基化程度更高，遗传改变较少。ZSCAN18 被鉴定为一种转录因子，可能参与细胞内的分子和代谢过程。ZSCAN18 低表达与细胞周期和糖酵解信号通路相关。ZSCAN18 的过表达抑制了与 Wnt/β-catenin 和糖酵解信号通路相关的基因的 mRNA 表达，包括 CTNNB1、BCL9、TSC1 和 PFKP。通过 TIMER 网络服务器和 TISIDB 参考，ZSCAN18 的表达与浸润性 B 细胞和树突状细胞（DC）呈负相关。ZSCAN18 的 DNA 甲基化与激活的 B 细胞、激活的 CD8+和 CD4+T 细胞、巨噬细胞、中性粒细胞和激活的 DC 呈正相关。此外，还鉴定出五个与 ZSCAN18 相关的枢纽基因（KDM6B、KAT6A、KMT2D、KDM1A 和 HSPBP1）。ZSCAN18、ZNF396 和 PGBD1 被鉴定为物理复合物的组成部分。