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

Oncogene (2026)Cite this article

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Abstract

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.

Proposed molecular mechanism: OTUB1-mediated deubiquitination stabilizes CDYL, which recruits EZH2 to deposit H3K27me3 at the SOX18 promoter, thereby repressing SOX18 expression and subsequent FDX1 transactivation, leading to cuproptosis suppression and lung cancer progression.

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Fig. 1: CDYL is upregulated in lung cancer and correlates with poor prognosis.
Fig. 2: CDYL overexpression enhances the malignant phenotypes of NSCLC cells.
Fig. 3: CDYL knockdown significantly suppresses tumor progression in lung cancer in vivo.
Fig. 4: CDYL confers resistance to cuproptosis in lung cancer cells.
Fig. 5: CDYL promotes cuproptosis resistance in lung cancer cells by inhibiting FDX1 expression.
Fig. 6: CDYL recruits EZH2 to promote H3K27me3-mediated repression of SOX18.
Fig. 7: CDYL alleviates SOX18-mediated transcriptional activation of FDX1 to inhibit lung cancer cell cuproptosis.
Fig. 8: OTUB1 stabilizes CDYL through deubiquitination to suppress cuproptosis.
Fig. 9: TTM reverses the antitumor effects of CDYL knockdown by restoring cuproptosis.

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References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  2. Debieuvre D, Molinier O, Falchero L, Locher C, Templement-Grangerat D, Meyer N, et al. Lung cancer trends and tumor characteristic changes over 20 years (2000–2020): results of three French consecutive nationwide prospective cohorts’ studies. Lancet Regional Health. 2022;22:100492

    Article  Google Scholar 

  3. Dohopolski M, Gottumukkala S, Gomez D, Iyengar P. Radiation therapy in non-small-cell lung cancer. Cold Spring Harbor Perspect Med. 2021;11:a037713

    Article  CAS  Google Scholar 

  4. Li Y, Yan B, He S. Advances and challenges in the treatment of lung cancer. Biomed Pharmacother. 2023;169:115891.

  5. Majeed U, Manochakian R, Zhao Y, Lou Y. Targeted therapy in advanced non-small cell lung cancer: current advances and future trends. J Hematol Oncol. 2021;14:108

    Article  PubMed  PubMed Central  Google Scholar 

  6. Su P-L, Furuya N, Asrar A, Rolfo C, Li Z, Carbone DP, et al. Recent advances in therapeutic strategies for non-small cell lung cancer. J Hematol Oncol. 2025;18:35

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chen R, Manochakian R, James L, Azzouqa A-G, Shi H, Zhang Y, et al. Emerging therapeutic agents for advanced non-small cell lung cancer. J Hematol Oncol. 2020;13:58.

  8. Lahn BT, Page DC. Retroposition of autosomal mRNA yielded testis-specific gene family on human Y chromosome. Nat Genet. 1999;21:429–33.

    Article  CAS  PubMed  Google Scholar 

  9. Shi Y, Sawada J, Sui G, Affar el B, Whetstine JR, Lan F, et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003;422:735–8.

    Article  CAS  PubMed  Google Scholar 

  10. Liu S, Yu H, Liu Y, Liu X, Zhang Y, Bu C, et al. Chromodomain protein CDYL acts as a crotonyl-CoA hydratase to regulate histone crotonylation and spermatogenesis. Mol Cell. 2017;67:853–66.e5.

    Article  CAS  PubMed  Google Scholar 

  11. Caron C, Pivot-Pajot C, van Grunsven LA, Col E, Lestrat C, Rousseaux S, et al. Cdyl: a new transcriptional co-repressor. EMBO Rep. 2003;4:877–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu Y, Lai S, Ma W, Ke W, Zhang C, Liu S, et al. CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression. Nat Commun. 2017;8:355.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Qin R, Cao S, Lyu T, Qi C, Zhang W, Wang Y. CDYL deficiency disrupts neuronal migration and increases susceptibility to epilepsy. Cell Rep. 2017;18:380–90.

    Article  CAS  PubMed  Google Scholar 

  14. Qi C, Liu S, Qin R, Zhang Y, Wang G, Shang Y, et al. Coordinated regulation of dendrite arborization by epigenetic factors CDYL and EZH2. J Neurosci. 2014;34:4494–508.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Mulligan P, Westbrook TF, Ottinger M, Pavlova N, Chang B, Macia E, et al. CDYL bridges REST and histone methyltransferases for gene repression and suppression of cellular transformation. Mol Cell. 2008;32:718–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kong J-G, Mei Z, Zhang Y, Xu L-Z, Zhang J, Wang Y. CDYL knockdown reduces glioma development through an antitumor immune response in the tumor microenvironment. Cancer Lett. 2023;567:216265.

  17. Cui Y, Zhao Y, Shen G, Lv Q, Ma L. CDYL loss promotes cervical cancer aggression by increasing PD-L1 expression via the suppression of IRF2BP2 transcription. Transl Oncol. 2024;47:102038.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Qiu Z, Zhu W, Meng H, Tong L, Li X, Luo P, et al. CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter. Theranostics. 2019;9:4717–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375:1254–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ge EJ, Bush AI, Casini A, Cobine PA, Cross JR, DeNicola GM, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer. 2021;22:102–13.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lutsenko S. Human copper homeostasis: a network of interconnected pathways. Curr Opin Chem Biol. 2010;14:211–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O’Halloran TV. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science. 1999;284:805–8.

    Article  CAS  PubMed  Google Scholar 

  23. Jawed R, Bhatti H. Cuproptosis in lung cancer: therapeutic options and prognostic models. Apoptosis. 2024;29:1393–8.

    Article  CAS  PubMed  Google Scholar 

  24. Kahlson MA, Dixon SJ. Copper-induced cell death. Science. 2022;375:1231–2.

    Article  CAS  PubMed  Google Scholar 

  25. Chen L, Min J, Wang F. Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Ther. 2022;7:378.

  26. Xie J, Yang Y, Gao Y, He J. Cuproptosis: mechanisms and links with cancers. Mol Cancer. 2023;22:46.

  27. Wang W, Wang X, Luo J, Chen X, Ma K, He H, et al. Serum copper level and the copper-to-zinc ratio could be useful in the prediction of lung cancer and its prognosis: a case-control study in Northeast China. Nutr Cancer. 2020;73:1908–15.

  28. Saleh SAK, Adly HM, Abdelkhaliq AA, Nassir AM. Serum levels of selenium, zinc, copper, manganese, and iron in prostate cancer patients. Curr Urol. 2020;14:44–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pavithra V, Sathisha TG, Kasturi K, Mallika DS, Amos SJ, Ragunatha S. Serum levels of metal ions in female patients with breast cancer. J Clin Diagn Res. 2015;9:BC25-c27.

  30. Basu S, Singh MK, Singh TB, Bhartiya SK, Singh SP, Shukla VK. Heavy and Trace Metals in Carcinoma of the Gallbladder. World J Surg. 2013;37:2641–6.

    Article  PubMed  Google Scholar 

  31. Yaman M, Kaya G, Yekeler H. Distribution of trace metal concentrations in paired cancerous and non-cancerous human stomach tissues. World J Gastroenterol. 2007;13:612–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kosova F, Cetin B, Akinci M, Aslan S, Seki A, Pirhan Y, et al. Serum copper levels in benign and malignant thyroid diseases. Bratisl Med J. 2012;113:718–20.

    Article  CAS  Google Scholar 

  33. Xue R, Qin C, Li L, Huang L, Tang K, Chen J, et al. SRF/SLC31A1 signaling promotes cuproptosis induced by celastrol in NSCLC. Int Immunopharmacol. 2025;148:114165.

  34. Xu H, Zhao Q, Cai D, Chen X, Zhou X, Gao Y, et al. o8G-modified circKIAA1797 promotes lung cancer development by inhibiting cuproptosis. J Exp Clin Cancer Res. 2025;44:110

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wang Y, Yao X, Lu Y, Ruan J, Yang Z, Wang C, et al. A PROTAC-based cuproptosis sensitizer in lung cancer therapy. Adv Mater. 2025;37:e2501435.

  36. Li D, Wang Y, Dong C, Chen T, Dong A, Ren J, et al. CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene. 2022;42:83–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu T, Jiang L, Tavana O, Gu W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 2019;79:1913–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Han X, Ren C, Lu C, Qiao P, Yang T, Yu Z. Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis. Cell Death Differ. 2022;29:1864–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li P, Sun Q, Bai S, Wang H, Zhao L. Combination of the cuproptosis inducer disulfiram and anti‑PD‑L1 abolishes NSCLC resistance by ATP7B to regulate the HIF‑1 signaling pathway. Int J Mol Med. 2023;53:19.

  40. Zhao J, Zhang W, Zeng Y, Lu D, Ma C, Zhang M, et al. Targeting ATP7A-dependent copper metabolic homeostasis induces cuproptosis and suppresses the progression of mutant KRAS-driven lung cancer. Cancer Res. 2025;85:3999–4017.

    Article  CAS  PubMed  Google Scholar 

  41. Sun Z, Xu H, Lu G, Yang C, Gao X, Zhang J, et al. AKT1 phosphorylates FDX1 to promote cuproptosis resistance in triple-negative breast cancer. Adv Sci. 2025;12:e2408106.

  42. Sun L, Zhang Y, Yang B, Sun S, Zhang P, Luo Z, et al. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer. Nat Commun. 2023;14:6523.

  43. Grimm D, Bauer J, Wise P, Krüger M, Simonsen U, Wehland M, et al. The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol. 2020;67:122–53.

    Article  CAS  PubMed  Google Scholar 

  44. Chen J, Dang Y, Feng W, Qiao C, Liu D, Zhang T, et al. SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7. Oncogene. 2020;39:5536–52.

    Article  CAS  PubMed  Google Scholar 

  45. Chen J, Feng W, Sun M, Huang W, Wang G, Chen X, et al. TGF-β1-induced SOX18 elevation promotes hepatocellular carcinoma progression and metastasis through transcriptionally upregulating PD-L1 and CXCL12. Gastroenterology. 2024;167:264–80.

    Article  CAS  PubMed  Google Scholar 

  46. Ling J, Wang S, Yi C, Zheng X, Zhou Y, Lou S, et al. PRMT1-mediated modification of H4R3me2a promotes liver cancer progression by enhancing the transcriptional activity of SOX18. Hepatol Commun. 2025;9:e0647.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Geng Q, Deng H, Fu J, Cui F. SOX18 exerts tumor-suppressive functions in papillary thyroid carcinoma through inhibition of Wnt/á-catenin signaling. Exp Cell Res. 2020;396:112249.

    Article  PubMed  Google Scholar 

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Funding

This study was supported by grants from the National Natural Science Foundation of China grants (Grant No. 82172351, Grant No. 82173018), and was sponsored by Natural Science Foundation of Henan Province (Grant No.232300421054), the Medical Science and Technology Provincial and Ministerial Co-construction Project of Henan province (Grant No. SBGJ202403034), the Henan Province Science and Technology Research and Development Joint Fund (242301420071).

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Authors and Affiliations

  1. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Ruike Zhang, Yang Li, Hongshen Lu, Xuanzhi Wang, Ying Zhu, Xiangzhuan Zhao, Keyu Jin, Lingxiu Meng, Zeduo Xu & Junhu Wan

  2. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Ruike Zhang & Hongyang Liu

  3. Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China

    Ruike Zhang & Huihui Gu

  4. School of Life Science, Zhengzhou University, Zhengzhou, Henan, China

    Huihui Gu

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Contributions

RZ, HYL, JW, and HG designed this study. RZ, YL, HSL, XW, YZ, and XZ performed the experiments. RZ, YL, KJ, LM, and ZX performed the data analysis. YL and JW reviewed the pathological data. RZ wrote the draft of the manuscript. YL, HG, and JW reviewed the manuscript. The authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hongyang Liu, Huihui Gu or Junhu Wan.

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This study was performed according to the ethical standards of the Declaration of Helsinki and received approval from the Ethics Committee at the First Affiliated Hospital of Zhengzhou University. Informed consent was obtained from all patients participating in this research.

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Zhang, R., Li, Y., Lu, H. et al. OTUB1/CDYL axis-mediated epigenetic repression of SOX18 facilitates lung cancer progression by inhibiting FDX1-dependent cuproptosis. Oncogene (2026). https://doi.org/10.1038/s41388-026-03748-2

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