NFX1‐123: A potential therapeutic target in cervical cancer

Abstract

AbstractNFX1‐123 is a splice variant isoform of the NFX1 gene. It is highly expressed in cervical cancers caused by HPV, and NFX1‐123 is a protein partner with the HPV oncoprotein E6. Together, NFX1‐123 and E6 affect cellular growth, longevity, and differentiation. The expression status of NFX1‐123 in cancers beyond cervical and head and neck cancers, and its potential as therapeutic target, have not been investigated. TSVdb of TCGA was used to quantify NFX1‐123 expression in 24 cancers compared with normal tissues. The NFX1‐123 protein structure was predicted and then submitted to retrieve suitable drug molecules. The top four compounds, found to bind in silico to NFX1‐123, were tested experimentally to determine their effects on NFX1‐123‐related cellular growth, survival, and migration. 46% of cancers (11 of 24 had significant differences in NFX1‐123 expression, with nine having had greater NFX1‐123 expression, when compared with adjacent normal tissues. Bioinformatics and proteomic predictive analysis modeled the three‐dimensional structure of NFX1‐123, and drug libraries were screened for high‐binding affinity compounds using this modeled structure. Seventeen drugs with binding energies ranging from −1.3 to −10 Kcal/mol were identified. The top four compounds were used to treat HPV‐ and HPV+ cervical cancer cell lines, three of which (Ropitoin, R428 and Ketoconazole) reduced NFX1‐123 protein levels, inhibited cellular growth, survival, and migration, and enhanced the cytotoxicity of Cisplatin. These findings highlight cancers expressing high levels of NFX1‐123, and drugs that target it, may reduce cellular growth, survival, and migration, making NFX1‐123 a potential novel therapeutic target.