2. Academic Validation
  3. Histone modification-regulated LncRNA DLEU1 interacts with ASCC2/ALKBH3 complex to drive DNA repair, antioxidant homeostasis and glucose metabolism in gastric cancer

Histone modification-regulated LncRNA DLEU1 interacts with ASCC2/ALKBH3 complex to drive DNA repair, antioxidant homeostasis and glucose metabolism in gastric cancer

  • Biomark Res. 2026 Jan 2;14(1):1. doi: 10.1186/s40364-025-00867-y.
Xiaoyan Zhang # 1 2 3,  Xin Wang # 1 2 3,  Qi Wang # 1 2 3,  Xu Wang # 1 2 3,  Hui Sun 1 2 3,  Yingxue Liu 1 2 3,  Cong Tan 1 2 3,  Shujuan Ni 1 2 3,  Weiwei Weng 1 2 3,  Meng Zhang 1 2 3,  Lei Wang 1 2 3,  Dan Huang 1 2 3,  Jie Chen 2 4,  Xiaoyu Wang 5,  Lu Gan 6,  Mierxiati Abudurexiti 7,  Wenfeng Wang 8 9,  Jinjia Chang 10 11,  Weiqi Sheng 12 13 14,  Midie Xu 15 16 17
Affiliations

Affiliations

  • 1 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 3 Institute of Pathology, Fudan University, Shanghai, 200032, China.
  • 4 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 5 Laboratory of Immunology and Virology, Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 6 Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai, 200032, China.
  • 7 Department of Urology, Shanghai Pudong New Area Gongli Hospital, Shanghai, 200135, China.
  • 8 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 9 Cancer Institute, Shanghai Urological Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai Cancer Center, Fudan University, Shanghai, 200032, China. [email protected].
  • 10 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 11 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 12 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 13 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 14 Institute of Pathology, Fudan University, Shanghai, 200032, China. [email protected].
  • 15 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. [email protected].
  • 16 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • 17 Institute of Pathology, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 41484982 DOI: 10.1186/s40364-025-00867-y
Abstract

Background: Long non-coding RNA (lncRNA) DLEU1 has been implicated in tumorigenesis, yet its mechanistic role in gastric Cancer (GC) remains elusive.

Methods: We investigated the epigenetic regulation and oncogenic function of DLEU1 in GC through chromatin immunoprecipitation, RNA-protein interaction assays, and functional analyses in organoids and xenograft models. The molecular mechanisms underlying DLEU1-mediated DNA repair and metabolic adaptation were elucidated using western blotting, quantitative RT-PCR, and luciferase reporter assays.

Results: DLEU1 was significantly upregulated in GC, driven by H3K27 acetylation and H3K4 methylation. Mechanistically, DLEU1 promoted DNA repair by facilitating ASCC2 nuclear translocation and its interaction with ALKBH3, thereby stabilizing E2F1 mRNA. In turn, E2F1 directly activated G6PD transcription, leading to enhanced NADPH production, redox homeostasis, and glucose metabolism. Functionally, co-targeting DLEU1 and ASCC2 synergized with G6PD inhibition, significantly impairing GC cells viability and tumor growth.

Conclusion: Our findings establish DLEU1 as a key oncogenic lncRNA in GC, orchestrating DNA repair, redox balance, and metabolic adaptation via the ASCC2-ALKBH3-E2F1-G6PD axis. Targeting this pathway may provide a promising therapeutic strategy for overcome GC chemoresistance.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40364-025-00867-y.

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