Emerging evidence implicates human endogenous retroviruses (HERVs) in cellular senescence and stemness suppression, suggesting that they may also play a role in tumor cell senescence. In this study, we identified the histone methyltransferase DOT1L as a key epigenetic repressor of HERV-K in adenocarcinoma of the esophagogastric junction (AEG). Comparison of expression of HERV and epigenetic regulators in AEG using two independent datasets revealed an inverse correlation between DOT1L and HERVs, and DOT1L was also overexpressed in AEG and correlated with poor clinical prognosis. Pharmacological inhibition of DOT1L in vitro and in vivo diminished H3K79 methylation, reactivated HERV-K expression, and triggered STING-dependent innate immune signaling, thereby inducing tumor cell senescence and conferring potent antitumor effects. By promoting the assembly and secretion of HERV-K-derived retrovirus-like particles (RVLPs), DOT1L inhibition propagated senescence to neighboring tumor cells via STING pathway activation. Together, this study not only establishes DOT1L as a druggable epigenetic target in AEG but also proposes a therapeutic strategy that leverages HERV-K and RVLPs to drive tumor cell senescence and intercellular senescence transmission for antitumor therapy.
Feng et al. (Tue,) studied this question.