Targeting DOT1L Reactivates HERV-K to Drive Cell-Autonomous and Paracrine Senescence in Adenocarcinoma of the Esophagogastric Junction

  • Cancer Res. 2026 Jul 15;86(14):3588-3603. doi: 10.1158/0008-5472.CAN-25-2437.
Huolun Feng  #  1  2  3 ,  Fa Ling  #  1  2  3 ,  Zhihui Xi  #  1  2  4 ,  Renjie Li  #  1  2  3 ,  Xi Lv  5 ,  Jieqing Guo  6 ,  Liping Su  6 ,  Jianlong Zhou  1  2 ,  Jiabin Zheng  1  2 ,  Fan Xing  6  7 ,  Yong Li  1  2  4  8
Affiliations
  • 1. Department of Gastrointestinal Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 2. Department of General Surgery, Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 3. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 4. School of Medicine, South China University of Technology, Guangzhou, China.
  • 5. Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
  • 6. Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
  • 7. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
  • 8. State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China.
  • # Contributed equally.
PMID: 42084229 DOI: 10.1158/0008-5472.CAN-25-2437
Abstract

Emerging evidence implicates human endogenous retroviruses (HERV) 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 disruptor of telomeric silencing 1-like (DOT1L) as a key epigenetic repressor of HERV-K in adenocarcinoma of the esophagogastric junction (AEG). Comparison of the 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. Pharmacologic 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 (RVLP), 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.

Significance: Pharmacological DOT1L inhibition not only reactivates HERV-K to trigger autonomous senescence through a STING-mediated immune response but also promotes formation of HERV-K-derived retrovirus-like particles that propagate senescence, suppressing gastrointestinal Cancer progression.

Products