Enhancer Clusters Drive Type I Interferon-Induced TRAIL Overexpression in Cancer, and Its Intracellular Protein Accumulation Fails to Induce Apoptosis.
Enhancer Clusters Drive Type I Interferon-Induced TRAIL Overexpression in Cancer, and Its Intracellular Protein Accumulation Fails to Induce Apoptosis.
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在干扰素刺激下，癌细胞上调促凋亡细胞因子 TRAIL，但这种上调的机制仍未解决。通过检查癌细胞中 TRAIL 的基因组调控景观，我们发现 TRAIL 与大而密集的调控增强子相关，并且这些有效的增强子簇介导癌细胞中干扰素驱动的 TRAIL 上调。在蛋白质水平上，我们令人惊讶地发现这种干扰素诱导的 TRAIL 不是分泌的。相反，它在细胞内积累，因此不能诱导癌细胞凋亡。因此，我们发现了一种涉及增强子簇的新型基因调控机制，该机制解释了癌细胞中经常遇到的 TRAIL 高水平表达。我们的结果还表明，干扰素诱导的 TRAIL 积累可能是某些癌症类型中细胞凋亡抵抗的一个因素，这是 TRAIL 以前未报道过的新作用，值得进一步研究。肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 是免疫细胞响应感染（通常响应干扰素 (IFN) 刺激）而产生和分泌的细胞因子。在癌症中，还显示IFN刺激TRAIL的产生，并且有人提出该TRAIL可以在不同的癌细胞中以自分泌或旁分泌的方式诱导细胞凋亡。然而，介导 TRAIL 上调的机制以及 TRAIL 作为癌细胞凋亡分子的影响仍然知之甚少。我们在此表明，在某些癌细胞中，TRAIL 被增强子簇上调，增强子簇是包含密集增强子的有效基因组调节区域，这些增强子具有组合和加性活性，并且通常被发现与促癌基因相关。此外，我们发现 IFNα 对 TRAIL 的上调是由乳腺癌和肺癌细胞中的这些增强子簇介导的。令人惊讶的是，IFNα 刺激导致这些癌细胞中 TRAIL 蛋白在细胞内积累。因此，该 TRAIL 不能诱导细胞凋亡。我们的研究为干扰素介导的 TRAIL 上调及其在癌细胞中蛋白质积累背后的机制提供了新的见解。需要进一步研究来了解细胞内 TRAIL 的作用或描述其介导癌细胞凋亡损伤的机制。
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.
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