In silico analysis of HOX-associated transcription factors as potential regulators of oral cancer

Objective: The objective of this study was identification of the transcription factor binding sites (TFBS) in the promoter of HOX genes and elucidation of the comprehensive interaction of transcription factors (TFs)/genes with HOX.

Methodology: Promoter sequences of HOXA3, HOXA5, HOXA9, HOXA10, HOXA13, HOXB5, HOXC10, HOXC12, and HOXD10 were analyzed to predict the TFBS and their targets using TRANSFAC, TRRUST, and Harmonizome. Functional analysis of the processed data sets was carried out using DAVID and GATHER gene annotation tools. A network of regulatory interactions was constructed using NetworkAnalyst and a comprehensive illustration of the TF-gene network was constructed with HOX as a central hub using the Encyclopedia of DNA Elements chromatin immunoprecipitation sequencing data. Further, the enriched network was constructed to elucidate the roles of these genes in the various pathways.

Results: Binding sites for E2F1, HNF3α, SP3, and KLF6 were common to promoter regions of all of the HOX genes. The functional annotation and pathway analysis elucidated the regulatory activity of a distinct set of TF-genes in interaction with HOX. A P value ≤.05 and false discovery rate ≤0.01 were considered statistically significant.

Conclusion: We have confirmed that the predicted TFBSs in the HOX gene promoters function in transcriptional regulation by modulating target gene activity. TF-gene interactions are crucial to understanding oral carcinogenesis.