Abstract:
Low doses of DNA methylation inhibitors (DNMTi), such as DAC, exert durable antitumor effects. In this study, we demonstrated that low doses of DAC exert anti-tumor effects, at least in part, by inducing TRAIL and TRAIL receptors. DAC-induced TRAIL signal regulates specific immune genes expression through NF-kB activation. Interestingly, TRAIL-induced NF-κB activation promotes further TRAIL production, creating a TRAIL autocrine loop. Furthermore, DAC-induced TRAIL signal mediates Cas3-dependent apoptosis-pyroptosis cascades. Thus, in cancer cells with methylation-mediated defective TRAIL signaling, TRAIL-TRAIL receptor signaling restoration using DAC, can promote dual effects: cancer cell immunomodulatory activity as well as cancer cell death through apoptosis and pyroptosis. Despite its promising anticancer activity, low-dose DAC therapy is associated with relatively low response rates. Induction of TRAIL itself along with its receptors may be a useful biomarker to predict responses to low-dose DAC therapy.
