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

• Type of Material: Article
• Authors: Allyson E. Koyen, Emory University; Matthew Z. Madden, Emory University; Dongkyoo Park, Emory University; Elizabeth Minten, Emory University; Priya Kapoor, Emory University; Erica Werner, Emory University; Neil T Pfister, Emory University; Ramona Haji-Seyed-Javadi, Emory University; Hui Zhang, Emory University; Jie Xu, Emory University; Nikita Deng, Emory University; Duc M. Duong, Emory University; Turner J. Pecen, Harvard TH Chan School of Public Health; Zoe Frazier, Brigham & Women's Hospital; Zachary D. Nagel, Harvard TH Chan School of Public Health; Jean-Bernard Lazaro, Brigham & Women's Hospital; Kent W. Mouw, Brigham & Women's Hospital; Nicholas Seyfried, Emory University; Carlos Moreno, Emory University; Taofeek Owonikoko, Emory University; Xingming Deng, Emory University; David Yu, Emory University
• Language: English
• Date: 2020-06-18
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41388-020-1332-2
• Title of Journal or Parent Work: ONCOGENE
• Volume: 39
• Issue: 25
• Start Page: 4798
• End Page: 4813
• Grant/Funding Information: This work was supported by NIH/NCI [R01CA178999 to D.S.Y., F31CA225119 to A.E.K, R01CA193828 to X.D., P01CA092584 to Z.D.N.]; NIH/NIEHS [U01ES029520 to Z.D.N.]; Lung Cancer Research Foundation [51347 and 60208 to D.S.Y]; Conquer Cancer Foundation of ASCO Young Investigator Award, supported by GO2 Foundation for Lung Cancer [15212 to N.T.P.]. 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.
• Keywords: Oncology; DNA-REPAIR; SELECTIVE-INHIBITION; LUNG-CANCER; OVARIAN-CANCER CELLS; NONCANONICAL FUNCTION; IN-VIVO; Biochemistry & Molecular Biology; METHYLATION; Life Sciences & Biomedicine; Genetics & Heredity; Science & Technology; GROUP PROTEIN EZH2; GENE-EXPRESSION; POLYCOMB; Cell Biology
• Research Categories: Biology, Genetics; Health Sciences, Oncology; Biology, Cell

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.