A New Role for Epigenetic Therapy

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Science Translational Medicine  17 Sep 2014:
Vol. 6, Issue 254, pp. 254ec159
DOI: 10.1126/scitranslmed.3010407

Epigenetics—a term that refers to long-term changes in gene expression not due to changes in the DNA sequence—has emerged as a therapeutic opportunity for many diseases, including diabetic retinopathy, cardiac dysfunction, and most notably cancer. The principal epigenetic mechanisms include (i) DNA methylation, (ii) histone modification, and (iii) microRNA regulation. Although microRNA-based therapies remain experimental, agents that alter DNA methylation or histone acetylation are widely used for treating various hematologic malignancies.

In cancer, epigenetic processes generally appear to down-regulate tumor suppressors and activate oncogenes. However, given the ubiquitous nature of epigenetic modulation, the expression of countless other genes within tumors is expected to be altered as well. In a recent report, Viet et al. have evaluated the role of epigenetic modification in mediating cancer pain by focusing on the mu-opioid receptor (OPRM1) gene pathway, which has an established role in pain processing. Examining clinical specimens from patients with oral cancer, they found that OPRM1 was methylated in cancer tissue, but not in matched normal tissue or in dysplastic tissue. In a mouse model of oral cancer, treatment with demethylating drugs such as decitabine resulted in reexpression of OPRM1 and secretion of β-endorphins in the tumors and associated neurons. These expression changes correlated with mechanical and thermal analgesic effects.

Demethylating drugs and other epigenetic modifiers alter the expression of many genes in different tissues. Harnessing the power of these therapies to optimize clinical benefit and limit toxicity requires careful assessment and balancing of these widespread effects. The recognition that epigenetic modification may control cancer pain—which reduces quality of life and often requires chronic use of toxic analgesic agents in hundreds of thousands of patients worldwide—represents a meaningful advance in the field.

C. T. Viet et al., Demethylating drugs as novel analgesics for cancer pain. Clin. Cancer Res. 10.1158/1078-0432.CCR-14-0901 (2014). [Abstract]

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