Re-expression of the methylated EDNRB gene in oral squamous cell carcinoma attenuates cancer-induced pain

Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ET_A) and endothelin B (ET_B) receptors, and is secreted in high concentrations in many different cancer environments. Although ET _A receptor activation has an established nociceptive effect in cancer models, the role of ET_B receptors on cancer pain is controversial. EDNRB, the gene encoding the ET_B receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. In this study we demonstrate that EDNRB is heavily methylated in human oral squamous cell carcinoma lesions, which are painful, but not methylated in human oral dysplasia lesions, which are typically not painful. ET_B mRNA expression is reduced in the human oral squamous cell carcinoma lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model, we show that ET_B receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.