Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer
Menée à l'aide d'une lignée cellulaire de carcinome du côlon, d'une xénogreffe sur un modèle murin et de données génétiques portant sur 7 288 tumeurs couvrant 21 cancers épithéliaux, cette étude met en évidence le rôle de régions amplificatrices issues de rétrovirus endogènes dans la dérégulation transcriptionnelle liée à la signalisation oncogène
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. Primate-specific endogenous retroviruses can reactivate as tumor-specific enhancers in colorectal cancer.