Epigenetic downregulation of the proapoptotic gene HOXA5 in oral squamous cell carcinoma.

Abstract

Homeobox A5 (HOXA5) 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 HOXA5 is one of the genes that are hypermethylated in oral tumor tissues. The present study obtained more‑complete information on the methylation status of HOXA5 by using the Illumina Infinium MethylationEPIC BeadChip and bisulfite sequencing assays. The results indicated that HOXA5 hypermethylation has great potential as a biomarker for detecting OSCC. Comparing HOXA5 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 HOXA5 expression in OSCC cell lines, verifying that the silencing of HOXA5 is primarily regulated by its hypermethylation. It was also found that upregulation of HOXA5 expression can not only increase OSCC cell death but that it can also enhance the therapeutic effect of cisplatin both in vitro and in vivo, suggesting that HOXA5 is an epigenetically downregulated proapoptotic gene in OSCC.