biostudies-literatureIvancevic ANCI NIH HHSNIGMS NIH HHSeado1218https://www.ebi.ac.uk/biostudies/studies/S-EPMC466953biostudies-literatureUnknown10(29)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 <i>ATG12</i> and <i>XRCC4</i>. Within the human population, individual LTR10 elementScience advancesEndogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer.PMC466953R37 CA261987T32 GM142607R35 GM128822Joyner OMBagby SMNguyen LLChuong EBIvancevic ASimpson DMBitler BGPitts TMfalseEndogenous 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 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 <i>ATG12</i> and <i>XRCC4</i>. Within the human population, individual LTR10 element2024-01-01T00:00:00Z2024 Jul2026-04-30T00:08:50.071Z2025-04-04T15:03:05.435ZS-EPMC4669533901839610.1126/sciadv.ado1218