ZNF468 Exhibits Oncogenic Activity by Regulating Unexplored ZNF707 in Breast Cancer

BACKGROUND: Dysregulation of transcription factors potentiates cancer cell proliferation, stemness, cellular plasticity, metastasis, and therapy resistance and also links with diagnosis/prognosis of the diseases. Thus, investigation of uncharacterized transcription factors is a prime aim for designing novel therapeutics. Large family C2H2 type zinc finger proteins (ZNFs) often bind to nucleic acids and also act as transcription factors. However, unregulated expression of these ZNFs was found to cause diverse pathological conditions including cancer. METHODS: Cancer database and specific GEO analysis were used to screen unexplored ZNFs. Subsequent knockdown and overexpression studies of selected ZNFs were conducted to examine their oncogenicity in breast cancer cells. Database analysis, ChIP, and knockdown study identified target genes. Overexpression and rescue experiments identified the oncogenic potential of target genes. The chemo-sensitivity of the target gene was determined. RT-qPCR analysis of breast cancer tissues confirms the oncogenic potential of the ZNFs. RESULTS: A systematic cancer database analysis using differential gene expressions (fold change between tumor and control tissue) and patient survivability (hazard ratio) found three unexplored ZNFs in breast cancer. Subsequent GEO database analysis determined ZNF468 for further experimentation. Knockdown of the gene ZNF468 showed inhibition of various oncogenic potentials including cell proliferation, migration, invasion, and epithelial to mesenchymal transition (EMT) and oncogenic markers (e.g., Bcl-2, Vimentin, and Zeb2) in both MCF-7 and MDA-MB-231 breast cancer cells. Database analysis found consensus DNA binding site of the ZNF468 in unexplored gene ZNF707, further confirmed by ChIP assay and knockdown of ZNF468. Subsequently, overexpression of ZNF707 gene upregulated cell proliferation, migration, invasion, and oncogenic markers in both MCF-7 and MDA-MB-231 cells. ZNF468 knockdown also inhibited the expression of various cholesterol regulatory genes. Furthermore, the oncogenic activity of ZNF468 in MCF-7 cells was revived by the overexpression of ZNF707. Overexpression of ZNF707 reduced the effectiveness of doxorubicin treatment. Finally, compared to benign, expression of both ZNF468 and ZNF707 was higher in malignant breast cancer patient tissue. CONCLUSIONS: These findings for the first time documented the oncogenic potential of ZNF707 in breast cancer. Additionally, ZNF468 promotes its oncogenic activity by regulating ZNF707 expression. Thus, these two ZNFs may be further explored to design promising therapy for breast cancer treatment.