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<p>Lung cancer persists as a major contributor to global cancer-related mortality, with metastasis, recurrence, and therapy resistance posing substantial barriers to effective disease management. CDYL has gained recognition as an epigenetic co-repressor involved in multiple dimensions of oncogenesis. However, its precise mechanistic contributions to non-small cell lung cancer (NSCLC) pathogenesis remain inadequately characterized. In this study, we observed pronounced CDYL overexpression in clinical NSCLC specimens, which exhibited a strong association with advanced disease staging and diminished patient survival. Functional profiling established that CDYL augments proliferative and migratory properties of NSCLC cells in vitro, whereas its genetic suppression markedly impaired tumor development in murine xenograft models. Mechanistically, we uncovered the deubiquitinating enzyme OTUB1 as a critical upstream effector that interacts with and stabilizes CDYL, thereby elevating its protein abundance. Further exploration demonstrated that CDYL confers cellular resistance to cuproptosis, a recently delineated copper-induced modality of regulated cell death. Through integrated transcriptomic and epigenomic interrogation, we elucidated that CDYL collaborates with EZH2 to promote H3K27me3 enrichment at the promoter region of the transcription factor SOX18, resulting in its transcriptional repression. Subsequent investigations revealed that SOX18 transcriptionally activates FDX1, a central regulator of cuproptosis. Consequently, CDYL-driven SOX18 repression leads to attenuated FDX1 expression, suppression of cuproptosis, and accelerated tumor progression. Importantly, administration of the copper chelator tetrathiomolybdate (TTM) counteracted the tumor-restraining consequences of CDYL ablation in vivo. Collectively, our findings unveil the OTUB1/CDYL/SOX18/FDX1 signaling cascade as a previously uncharacterized regulatory circuit that facilitates lung cancer progression through cuproptosis inhibition, providing new insights into the epigenetic regulation of cuproptosis and identifying potential therapeutic targets for NSCLC.</p><p></p>

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OTUB1/CDYL axis-mediated epigenetic repression of SOX18 facilitates lung cancer progression by inhibiting FDX1-dependent cuproptosis

  • 期刊论文

  • 发表日期：

    2026年3月30日

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  • Ruike Zhang,
  • Yang Li,
  • Hongshen Lu,
  • Xuanzhi Wang,
  • Ying Zhu,
  • Xiangzhuan Zhao,
  • Keyu Jin,
  • Lingxiu Meng,
  • Zeduo Xu,
  • Hongyang Liu,
  • Huihui Gu,
  • Junhu Wan

摘要

Lung cancer persists as a major contributor to global cancer-related mortality, with metastasis, recurrence, and therapy resistance posing substantial barriers to effective disease management. CDYL has gained recognition as an epigenetic co-repressor involved in multiple dimensions of oncogenesis. However, its precise mechanistic contributions to non-small cell lung cancer (NSCLC) pathogenesis remain inadequately characterized. In this study, we observed pronounced CDYL overexpression in clinical NSCLC specimens, which exhibited a strong association with advanced disease staging and diminished patient survival. Functional profiling established that CDYL augments proliferative and migratory properties of NSCLC cells in vitro, whereas its genetic suppression markedly impaired tumor development in murine xenograft models. Mechanistically, we uncovered the deubiquitinating enzyme OTUB1 as a critical upstream effector that interacts with and stabilizes CDYL, thereby elevating its protein abundance. Further exploration demonstrated that CDYL confers cellular resistance to cuproptosis, a recently delineated copper-induced modality of regulated cell death. Through integrated transcriptomic and epigenomic interrogation, we elucidated that CDYL collaborates with EZH2 to promote H3K27me3 enrichment at the promoter region of the transcription factor SOX18, resulting in its transcriptional repression. Subsequent investigations revealed that SOX18 transcriptionally activates FDX1, a central regulator of cuproptosis. Consequently, CDYL-driven SOX18 repression leads to attenuated FDX1 expression, suppression of cuproptosis, and accelerated tumor progression. Importantly, administration of the copper chelator tetrathiomolybdate (TTM) counteracted the tumor-restraining consequences of CDYL ablation in vivo. Collectively, our findings unveil the OTUB1/CDYL/SOX18/FDX1 signaling cascade as a previously uncharacterized regulatory circuit that facilitates lung cancer progression through cuproptosis inhibition, providing new insights into the epigenetic regulation of cuproptosis and identifying potential therapeutic targets for NSCLC.