Exploring the Significance of the Exon 4-Skipping Isoform of the ZNF217 Oncogene in Breast Cancer

Abstract

Oncogene alternative splicing events can create distinct functional transcripts that offer new candidate prognostic biomarkers for breast cancer. ZNF217 is a well-established oncogene but its exon 4-skipping isoform (ZNF217-ΔE4) has never been investigated in terms of clinical or biological relevance. Using in silico RNA-seq and RT-qPCR analyses, we demonstrated for the first time the existence of ZNF217-ΔE4 transcripts in primary breast tumors, and a positive correlation between ZNF217-ΔE4 mRNA levels and those of the wild-type oncogene (ZNF217-WT). A pilot retrospective analysis revealed that, in the Luminal subclass, the combination of the two ZNF217 variants (the ZNF217-ΔE4-WT gene-expression signature) provided more information than the mRNA expression levels of each isoform alone. Ectopic overexpression of ZNF217-ΔE4 in breast cancer cells promoted an aggressive phenotype and an increase in ZNF217-WT expression levels that was inversely correlated with DNA methylation of the ZNF217 gene. This study provides new insights into the possible role of the ZNF217-ΔE4 splice variant in breast cancer and suggests a close interplay between the ZNF217-WT and ZNF217-ΔE4 isoforms. Our data suggest that a dual signature combining the expression levels of these two isoforms may serve as a novel prognostic biomarker allowing better stratification of breast cancers with good prognosis and aiding clinicians in therapeutic decisions.

In silico identification and in vitro evaluation of MRPS30‐DT lncRNA and MRPS30 gene expression in breast cancer

“…Transcriptional enrichment analysis revealed that MRPS30‐DT might be associated the most with ZNF217 and FoxM1, whose roles in breast cancer have been demonstrated in the literature. Studies have demonstrated that ZNF217 acts as an oncogene in breast cancer cell lines by promoting cell proliferation, invasiveness, and chemotherapy resistance 54 . FoxM1 as an oncogenic transcription factor was associated with poor survival in breast cancer patients and can be used as a potential biomarker for targeted therapies and prognosis assessment in breast cancer patients 55–57 …”

“…Studies have demonstrated that ZNF217 acts as an oncogene in breast cancer cell lines by promoting cell proliferation, invasiveness, and chemotherapy resistance. 54 FoxM1 as an oncogenic transcription factor was associated with poor survival in breast cancer patients and can be used as a potential biomarker for targeted therapies and prognosis assessment in breast cancer patients. [55][56][57] Disease enrichment analysis of co-expressed genes revealed that the most enriched diseases were mammary neoplasms, renal cell dysplasia, and breast carcinoma.…”

The Intricate Interplay between the ZNF217 Oncogene and Epigenetic Processes Shapes Tumor Progression

“…In ER+ BCa cells, ERα signaling disruption by a siRNA strategy triggered epigenetic silencing (hypermethylation) of the ZNF217 gene [ 36 ]. More recently, ectopic overexpression in BCa cells of the exon 4-skipping isoform of ZNF217 (ZNF217-ΔE4) was shown to promote high ZNF217 wild-type expression levels that were inversely correlated with DNA methylation of the ZNF217 gene at key CpG sites [ 38 ].…”

“…Given the importance of DNA methylation in gene expression regulation, further studies would be required to elucidate whether the co-operation between ZNF217 and CoREST/DNMT3A is also involved in the epigenetic regulation of key genes implicated in ZNF217-dependent programs. Finally, as ZNF217-ΔE4 isoform was associated with deregulated DNA methylation of the ZNF217 gene at key CpG sites [ 38 ], it would be important to decipher whether the ZNF217-ΔE4 isoform may co-operate with the DNA methylation/demethylation machinery.…”