Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the mechanisms underlying the formation of these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are a rich source of enhancers displaying cancer-specific activity. In colorectal cancer and other epithelial tumors, oncogenic MAPK/AP1 signaling drives the activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements regulate tumor-specific expression of multiple genes associated with tumorigenesis, such as ATG12 and XRCC4 . Within the human population, individual LTR10 elements exhibit germline and somatic structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers contribute to transcriptional dysregulation in response to oncogenic signaling and shape the evolution of cancer-specific regulatory networks.

中文翻译：

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内源性逆转录病毒介导转录重连以响应结直肠癌中的致癌信号


癌细胞表现出重新连接的转录调控网络，促进肿瘤生长和存活。然而，这些病理网络形成的机制仍然知之甚少。通过泛癌表观基因组分析，我们发现灵长类动物特异性内源性逆转录病毒（ERV）是具有癌症特异性活性的增强子的丰富来源。在结直肠癌和其他上皮肿瘤中，致癌 MAPK/AP1 信号传导驱动源自灵长类特异性 ERV 家族 LTR10 的增强子的激活。结直肠癌细胞的功能研究表明，LTR10 元件调节与肿瘤发生相关的多个基因的肿瘤特异性表达，例如ATG12和XRCC4 。在人类群体中，单个 LTR10 元件表现出种系和体细胞结构变异，这是由高度可变的内部串联重复区域引起的，这会影响 AP1 结合活性。我们的研究结果表明，ERV 衍生的增强子会导致转录失调，以响应致癌信号，并塑造癌症特异性调控网络的进化。