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EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair

Oncogene volume 39, pages 4798–4813 (2020)Cite this article

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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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Fig. 1: A siRNA screen targeting nuclear enzymes identifies genes that mediate cisplatin resistance in SCLC.
Fig. 2: EZH2 mediates cisplatin resistance in SCLC.
Fig. 3: EZH2 localizes to and promotes repair of UV-induced CPD lesions.
Fig. 4: EZH2 interacts with and is epistatic with DDB1–DDB2 in sensitizing SCLC cells to cisplatin and UV.
Fig. 5: EZH2 promotes the stability of DDB2 independent of its catalytic activity and PRC2.
Fig. 6: DDB2 functions downstream of EZH2 in NER and in mediating cisplatin resistance in SCLC.
Fig. 7: EZH2 depletion with DZNep sensitizes SCLC to cisplatin in vitro and in vivo and model for EZH2 in NER.

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Acknowledgements

EmGFP-EZH2 WT plasmid was a gift of Damian Yap (British Colombia Cancer Research Center) [52]. EZH2 PRC2 mutant plasmids were a gift of Lixin Wan (Moffit Cancer Center) [56]. FLAG-DDB2 plasmid was a gift of Qi-En Wang (The Ohio State University) [55].

Funding

This work was supported by NIH/NCI [R01CA178999 to DSY, F31CA225119 to AEK, R01CA193828 to XD, P01CA092584 to ZDN]; NIH/NIEHS [U01ES029520 to ZDN]; Lung Cancer Research Foundation [51347 and 60208 to DSY]; Conquer Cancer Foundation of ASCO Young Investigator Award, supported by GO2 Foundation for Lung Cancer [15212 to NTP]. Any opinions, findings, and conclusions expressed in this material are those of the author(s) and do not necessarily reflect those of the ASCO®, Conquer Cancer®, or GO2 Foundation for Lung Cancer.

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Authors and Affiliations

  1. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Allyson E. Koyen, Matthew Z. Madden, Dongkyoo Park, Elizabeth V. Minten, Priya Kapoor-Vazirani, Erica Werner, Neil T. Pfister, Ramona Haji-Seyed-Javadi, Hui Zhang, Jie Xu, Nikita Deng, Xingming Deng & David S. Yu

  2. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Duc M. Duong & Nicholas T. Seyfried

  3. Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA

    Turner J. Pecen & Zachary D. Nagel

  4. Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, MA, 02215, USA

    Zoë Frazier, Jean-Bernard Lazaro & Kent W. Mouw

  5. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Carlos S. Moreno

  6. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Taofeek K. Owonikoko

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Conceptualization, AEK, MZM, and DSY; Investigation, AEK, MZM, DP, EVM, PK, EW, NTP, RHJ, HZ, JX, ND, TJP, ZF, DMD, JL, and CSM; Writing—Original draft, AEK and DSY; Writing—Review and editing, AEK, MZM, DP, EVM, PK, EW, NTP, RHJ, HZ, JX, ND, DMD, TJP, ZF, ZDN, JL, KWM, NTS, CSM, TKO, XD, and DSY; Supervision—JL, ZDN, KWM, NTS, CSM, TKO, XD, and DSY; Funding acquisition, AEK, NTP, ZDN, XD, and DSY.

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Correspondence to David S. Yu.

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Koyen, A.E., Madden, M.Z., Park, D. et al. EZH2 has a non-catalytic and PRC2-independent role in stabilizing DDB2 to promote nucleotide excision repair. Oncogene 39, 4798–4813 (2020). https://doi.org/10.1038/s41388-020-1332-2

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  • DOI: https://doi.org/10.1038/s41388-020-1332-2

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