Epigenetic downregulation of the proapoptotic gene <i>HOXA5</i> in oral squamous cell carcinoma

Homeobox A5 (<i>HOXA5</i>) has been identified as a tumor suppressor gene in breast cancers, but its role in oral squamous cell carcinoma (OSCC) has not been confirmed. The Illumina GoldenGate Assay for methylation identified that DNA methylation patterns differ between tumorous and normal tissues in the oral cavity and that <i>HOXA5</i> is one of the genes that are hypermethylated in oral tumor tissues. The present study obtained more‑complete information on the methylation status of <i>HOXA5</i> by using the Illumina Infinium MethylationEPIC BeadChip and bisulfite sequencing assays. The results indicated that <i>HOXA5</i> hypermethylation has great potential as a biomarker for detecting OSCC. Comparing <i>HOXA5</i> RNA expression between normal oral tissue and OSCC tissue samples indicated that its median level was 2.06‑fold higher in normal tissues that in OSCC tissues. Moreover, treatment using the demethylating agent 5‑aza‑2'‑deoxycytidine can upregulate <i>HOXA5</i> expression in OSCC cell lines, verifying that the silencing of <i>HOXA5</i> is primarily regulated by its hypermethylation. It was also found that upregulation of <i>HOXA5</i> expression can not only increase OSCC cell death but that it can also enhance the therapeutic effect of cisplatin both <i>in vitro</i> and <i>in vivo</i>, suggesting that <i>HOXA5</i> is an epigenetically downregulated proapoptotic gene in OSCC.