Targeting DOT1L reactivates HERV-K to drive paracrine senescence via retrovirus-like particles in adenocarcinoma of the esophagogastric junction
Recent evidence suggests that HERVs can induce cellular senescence and suppress cellular stemness, yet their role in tumor senescence remains unexplored. In this study, we identified DOT1L as a negative regulatory methyltransferase of HERV-K in adenocarcinoma of the esophagogastric junction (AEG), whose overexpression correlates with poor prognosis. Through both in vitro and in vivo experiments, pharmacological inhibition of DOT1L reduced H3K79 methylation, reactivated HERV-K, and triggered a viral mimicry response that induced senescence, resulting in significant anti-tumor efficacy. Furthermore, we demonstrated that DOT1L inhibitors promote the formation of HERV-K-derived retrovirus-like particles (RVLPs). These RVLPs are secreted extracellularly, infect neighboring cells, and initiate a cascade of paracrine senescence via the STING signaling pathway. These findings not only provide a rationale for DOT1L as a prognostic marker and therapeutic target for AEG, but also open up a new direction for epigenetic tumor therapy strategies based on ERVs reactivation.