Epigenetic silencing of ZIC4 unveils a potential tumor suppressor role in pediatric choroid plexus carcinoma

• Published in: Scientific reports 2024-09, Vol.14 (1), p.21293-13, Article 21293
• Main Authors: Hesham, Dina, Mosaab, Amal, Amer, Nada, Al-Shehaby, Nouran, Magdeldin, Sameh, Hassan, Ahmed, Georgiev, Hristo, Elshoky, Hisham, Rady, Mona, Aisha, Khaled Abou, Sabet, Ola, El-Naggar, Shahenda
• Format: Article
• Language: English
• Subjects: 631/337; 631/67; 631/80; Antigen presentation; Antigen processing; Bioinformatics; Bisulfite; Carcinoma; Carcinoma - genetics; Carcinoma - metabolism; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Child; Child, Preschool; Choroid plexus; Choroid Plexus Neoplasms - genetics; Choroid Plexus Neoplasms - metabolism; Choroid Plexus Neoplasms - pathology; Data mining; DNA Methylation; Endoplasmic reticulum; Epigenesis, Genetic; Epigenetic silencing; Epigenetics; Female; Gene Expression Regulation, Neoplastic; Gene regulation; Gene Silencing; Genes, Tumor Suppressor; Histone methyltransferase; Humanities and Social Sciences; Humans; Immune response; Infant; Male; Medical prognosis; multidisciplinary; Nerve Tissue Proteins; Overexpression; Pediatric choroid plexus carcinoma; Pediatrics; Prognosis; Proteomic profiling; Proteomics; RNA processing; RNA-mediated interference; Science; Science (multidisciplinary); Therapeutic targets; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptomic profiling; Tumor suppressor; Tumor suppressor genes; Tumors; ZIC4
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-71188-7

Zic family member ZIC4 is a transcription factor that has been shown to be silenced in several cancers. However, understanding the regulation and function of ZIC4 in pediatric choroid plexus tumors (CPTs) remained limited. This study employed data mining and bioinformatics analysis to investigate the DNA methylation status of ZIC4 in CPTs and its correlation with patient survival. Our results unveiled ZIC4 methylation as a segregating factor, dividing CPT cohorts into two clusters, with hyper-methylation linked to adverse prognosis. Hyper-methylation of ZIC4 was confirmed in a choroid plexus carcinoma-derived cell line (CCHE-45) by bisulfite sequencing. Furthermore, our study demonstrated that demethylating agent and a histone methyltransferase inhibitor could reverse ZIC4 silencing. RNA sequencing and proteomic analysis showed that ZIC4 over-expression influenced genes and proteins involved in immune response, antigen processing and presentation, endoplasmic reticulum stress, and metabolism. Functionally, re-expressing ZIC4 negatively impacted cell proliferation and migration. Ultimately, these findings underscore ZIC4 hyper-methylation as a prognostic marker in CPTs and shed light on potential mechanisms underlying its tumor suppressor role in CPC. This insight paves the way for novel therapeutic targets in treating aggressive CPTs.