Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer
Ivancevic A., et al. (2024). Endogenous retroviruses mediate transcriptional rewiring in response to oncogenic signaling in colorectal cancer. Sci. Adv. DOI: 10.1126/sciadv.ado1218
Transposable elements (TEs), including endogenous retroviruses (ERVs), are repetitive genetic sequences that can move within the genome. Although often silenced in healthy cells, these elements can become reactivated in diseases such as cancer, where they contribute to genomic instability and dysregulated gene expression. ERVs, a subclass of TEs, are viral sequences that integrated into the genome millions of years ago. Their reactivation in cancer has been linked to transcriptional changes that promote tumor development and progression.
This study explores the role of ERVs in mediating transcriptional changes in colorectal cancer in response to oncogenic signaling. Using a pan-cancer epigenomic analysis, the researchers identified that long terminal repeat (LTR) elements derived from primate-specific ERVs, particularly the LTR10 family, act as enhancers in colorectal cancer and other epithelial tumors. These enhancers become active through oncogenic MAPK/AP1 signaling, regulating tumor-specific genes such as ATG12 and XRCC4, both linked to cancer progression and treatment resistance.
The study used both in vitro and patient-derived colorectal cancer samples, discovering that LTR10 elements show histone modifications indicative of enhancer activity. Furthermore, LTR10 enhancer activation varies based on the cancer subtype and the presence of MAPK signaling. The authors demonstrated the functional relevance of these LTR10 enhancers in regulating tumor-specific gene expression. Disruption of these elements altered gene expression, providing insights into cancer-specific regulatory networks and suggesting potential targets for therapeutic interventions.
Keywords: Endogenous retroviruses, transcriptional rewiring, oncogenic signaling, colorectal cancer, MAPK signaling, AP1, enhancers, LTR10, tumor-specific gene regulation.
