부산대학교 도서관

Simple Summary: Upon interferon stimulation, cancer cells upregulate the pro-apoptotic cytokine TRAIL, but the mechanism of this upregulation remains unresolved. By examining the genomic regulatory landscape of TRAIL in cancer cells, we found that TRAIL is associated with large, densely clustered regulatory enhancers and that these potent enhancer clusters mediate the interferon-driven upregulation of TRAIL in cancer cells. At the protein level, we, surprisingly, found that this interferon-induced TRAIL is not secreted. Instead, it accumulates intracellularly and is thus not capable of inducing apoptosis in cancer cells. Thus, we identified a novel gene regulatory mechanism involving enhancer clusters that explains the high levels of TRAIL expression often encountered in cancer cells. Our results also suggest that the accumulation of interferon-induced TRAIL may be a factor contributing to apoptosis resistance in certain cancer types, a new role that has not been reported for TRAIL before, which deserves further investigation. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine produced and secreted by immune cells in response to an infection, often in response to interferon (IFN) stimulation. In cancer, it has also been shown that IFN stimulates the production of TRAIL, and it has been proposed that this TRAIL can induce apoptosis in an autocrine or paracrine manner in different cancer cells. Yet, the mechanism mediating TRAIL upregulation and the implications of TRAIL as an apoptotic molecule in cancer cells are still poorly understood. We show here that in certain cancer cells, TRAIL is upregulated by enhancer clusters, potent genomic regulatory regions containing densely packed enhancers that have combinatorial and additive activity and that are usually found to be associated with cancer-promoting genes. Moreover, we found that TRAIL upregulation by IFNα is mediated by these enhancer clusters in breast and lung cancer cells. Surprisingly, IFNα stimulation leads to the intracellular accumulation of TRAIL protein in these cancer cells. Consequently, this TRAIL is not capable of inducing apoptosis. Our study provides novel insights into the mechanism behind the interferon-mediated upregulation of TRAIL and its protein accumulation in cancer cells. Further investigation is required to understand the role of intracellular TRAIL or depict the mechanisms mediating its apoptosis impairment in cancer cells. [ABSTRACT FROM AUTHOR]