Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer

Cancer cells exhibit rewired transcriptional regulatory networks that promote tumor growth and survival. However, the processes that configure these pathological networks remain poorly understood. Through a pan-cancer epigenomic analysis, we found that primate-specific endogenous retroviruses (ERVs) are an abundant source of enhancers that show cancer-specific activity. In colorectal cancer and other epithelial tumors, oncogenic MAPK/AP1 signaling drives activation of enhancers derived from the primate-specific ERV family LTR10. Functional studies in colorectal cancer cells revealed that LTR10 elements are involved in regulating multiple genes associated with tumorigenesis, including ATG12 . Within the human population, individual LTR10 elements show frequent structural variation resulting from a highly mutable internal tandem repeat region, which affects AP1 binding activity. Our findings reveal that ERV-derived enhancers mediate transcriptional dysregulation in response to oncogenic signaling, and shape the evolution of cancer-specific regulatory networks. ### Competing Interest Statement The authors have declared no competing interest.