ArticleOncogene2020
EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair.
Article in Oncogene, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 53 citations in OpenAlex.
- Structural characteristics and SARs of EZH2 inhibitors.Molecular diversity · 2026Review
- Unveiling the New Trick for Epigenetic Drug: Radiation Enhancement of Prostate Cancer by the EZH2 Inhibitor Tazemetostat.Journal of cellular and molecular medicine · 2026Article
- Mechanisms of resistance in small cell lung cancer.Chinese medical journal · 2026Review
- A dual role of EZH2 in regulating A-to-I RNA editing and mRNA stability through ADAR.Nature communications · 2026Article
- Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The deubiquitinase OTUD1 orchestrates cisplatin chemosensitivity of non-small cell lung cancer through destabilizing RAD23B/XPC.Oncogene · 2025Article
- Oncogenic and immunomodulatory functions of SUV420H1 in HPV-negative head and neck squamous cell carcinoma.bioRxiv : the preprint server for biology · 2025Article
- NAMPT haploinsufficiency is a collateral lethal therapeutic vulnerability in high-risk myeloid malignancies withBlood neoplasia · 2025Article
- Role of epigenetics in paediatric cancer pathogenesis & drug resistance.British journal of cancer · 2025Review
- Current and future therapies for small cell lung carcinoma.Journal of hematology & oncology · 2025Review
- Chlorogenic acid targets SIRT6 to relieve UVB - induced UV damage.Archives of dermatological research · 2025Article
- Intratumoral heterogeneity and potential treatment strategies in small cell lung cancer.Frontiers in oncology · 2025Review
- Exploring oncogenic roles and clinical significance of EZH2: focus on non-canonical activities.Therapeutic advances in medical oncology · 2025Review
- PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis.BMC cancer · 2024Article
- Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2.European journal of medicinal chemistry · 2024Article
- Role and potential therapeutic value of histone methyltransferases in drug resistance mechanisms in lung cancer.Frontiers in oncology · 2024Review
- Exploring the therapeutic potential of targeting polycomb repressive complex 2 in lung cancer.Frontiers in oncology · 2023Review
- Transient Polycomb activity represses developmental genes in growing oocytes.Clinical epigenetics · 2022Article
- EZH2 Inhibition and Cisplatin as a Combination Anticancer Therapy: An Overview of Preclinical Studies.Cancers · 2022Review
- SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk.Cancer discovery · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
22 authors at 3 institutions in 1 country.
Funding
Abstract
Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor outcomes associated with resistance to cisplatin-based chemotherapy. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2), which silences transcription through trimethylation of histone H3 lysine 27 (H3K27me3) and has emerged as an important therapeutic target with inhibitors targeting its methyltransferase activity under clinical investigation. Here, we show that EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair (NER) and govern cisplatin resistance in SCLC. Using a synthetic lethality screen, we identified important regulators of cisplatin resistance in SCLC cells, including EZH2. EZH2 depletion causes cellular cisplatin and UV hypersensitivity in an epistatic manner with DDB1-DDB2. EZH2 complexes with DDB1-DDB2 and promotes DDB2 stability by impairing its ubiquitination independent of methyltransferase activity or PRC2, thereby facilitating DDB2 localization to cyclobutane pyrimidine dimer crosslinks to govern their repair. Furthermore, targeting EZH2 for depletion with DZNep strongly sensitizes SCLC cells and tumors to cisplatin. Our findings reveal a non-catalytic and PRC2-independent function for EZH2 in promoting NER through DDB2 stabilization, suggesting a rationale for targeting EZH2 beyond its catalytic activity for overcoming cisplatin resistance in SCLC.
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