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

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

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.

Keywords: DNA methylation; ZSCAN18; breast cancer; integrated analysis; transcription regulation; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Breast Neoplasms* / genetics
  • DNA Methylation
  • Female
  • Histone Acetyltransferases
  • Histone Demethylases
  • Humans
  • Jumonji Domain-Containing Histone Demethylases
  • RNA, Messenger
  • Tumor Microenvironment
  • Zinc Fingers*

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Histone Acetyltransferases
  • Histone Demethylases
  • HSPBP1 protein, human
  • Jumonji Domain-Containing Histone Demethylases
  • KAT6A protein, human
  • KDM1A protein, human
  • KDM6B protein, human
  • RNA, Messenger
  • ZSCAN18 protein, human

Grants and funding

This research was funded by National Natural Science Foundation of China (grant number: 81903000), Natural Science Foundation of Sichuan Province (grant number: 2022NSFSC1425), Luzhou - Southwest Medical University Applied Basic Research Project (grant number: 2019LZXNYDJ07), and Southwest Medical University Scientific Research Project (grant number: 2021ZKQN053).