Issues

Pharmacologic disruption of epigenetic enzymes such as DNA methyltransferases, histone methyltransferases, and histone acetyltransferases has shown some efficacy in cancer, likely in part due to their ability to reactivate normally silenced genomic regions. Endogenous retroviruses are among the regions often activated, resulting in a RIG-I–MDA5-dependent innate immune response. Additionally, Fresquet and colleagues found that the helicase activity of RIG-I and MDA5 depleted intracellular ATP, reversing the Warburg effect and increasing cancer cell dependence on aerobic glycolysis. This was associated with succinate dehydrogenase hyperactivation and consequent production of reactive oxygen species, leading to caspase-independent tumor cell necroptosis that could be enhanced by blocking the programmed-cell-death inhibitor BCL2. For more information, see the article by Fresquet and colleagues on page 1268.