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Methylation-dependent and -independent roles of EZH2 synergize in CDCA8 activation in prostate cancer

Oncogene volume 41, pages 1610–1621 (2022)Cite this article

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Abstract

Cell division cycle-associated 8 (CDCA8) is a component of chromosomal passenger complex (CPC) that participates in mitotic regulation. Although cancer-related CDCA8 hyperactivation has been widely observed, its molecular mechanism remains elusive. Here, we report that CDCA8 overexpression maintains tumorigenicity and is associated with poor clinical outcome in patients with prostate cancer (PCa). Notably, enhancer of zeste homolog 2 (EZH2) is identified to be responsible for CDCA8 activation in PCa. Genome-wide assays revealed that EZH2-induced H3K27 trimethylation represses let-7b expression and thus protects the let-7b-targeting CDCA8 transcripts. More importantly, EZH2 facilitates the self-activation of E2F1 by recruiting E2F1 to its own promoter region in a methylation-independent manner. The high level of E2F1 further promotes transcription of CDCA8 along with the other CPC subunits. Taken together, our study suggests that EZH2-mediated cell cycle regulation in PCa relies on both its methyltransferase and non-methyltransferase activities.

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Fig. 1: Elevated CDCA8 expression in PCa.
Fig. 2: CDCA8 sustains tumorigenicity of PCa.
Fig. 3: Expression of CDCA8 is positively correlated with EZH2 in PCa.
Fig. 4: EZH2 is a master regulator of cell cycle-related genes including CDCA8.
Fig. 5: EZH2-mediated let-7b repression increases CDCA8 level in PCa.
Fig. 6: EZH2 facilitates self-activation of E2F1 and thus promotes transcription of all CPC members.

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Data availability

Next generation sequencing data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO) under accession code GSE184740. Our previously published RNA-seq data of EZH2-deficient C4-2 cells are available under accession code GSE143975. Previously published ChIP-seq data of LNCaP and its derived LNCaP-abl cells that were re-analyzed here are available under accession codes GSE107782 (EZH2 and H3K27me3) and GSE67809 (E2F1).

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Acknowledgements

This work was supported by American Cancer Society (RSG-15-192-01) and a startup funding provided by the Northwestern University. Part of effort for QC was supported by Northwestern University, U.S. Department of Defense (W81XWH-17-1-0357, W81XWH-19-1-0563 and W81XWH-20-1-0504), NIH/NCI (R01CA208257, R01CA256741 and Prostate SPORE P50CA180995 Development Research Program) and Polsky Urologic Cancer Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University at Northwestern Memorial Hospital.

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Author notes

  1. These authors contributed equally: Yang Yi, Yanqiang Li, Chao Li.

Authors and Affiliations

  1. Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA

    Yang Yi, Chao Li, Longxiang Wu, Rui Wang & Qi Cao

  2. Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, TX, 77030, USA

    Yang Yi, Chao Li & Qi Cao

  3. Basic and Translational Research Division, Department of Cardiology, Boston Children’s Hospital, Boston, MA, 02115, USA

    Yanqiang Li, Dongyu Zhao & Kaifu Chen

  4. Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA

    Yanqiang Li, Dongyu Zhao & Kaifu Chen

  5. Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Chao Li & Long Wang

  6. Department of Urology, Xiangya Hospital of Central South University, Changsha, 410008, China

    Longxiang Wu

  7. Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, China

    Fuxi Li & Wei Zhao

  8. Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada

    Ladan Fazli & Xuesen Dong

  9. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada

    Ladan Fazli & Xuesen Dong

  10. Prostate Cancer Program, Dana-Farber Harvard Cancer Center, 450 Brookline Avenue, BP332A, Boston, MA, USA

    Kaifu Chen

  11. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA

    Qi Cao

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  1. Yang Yi
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Contributions

YY and QC conceived and designed the research with the help of WZ; YY performed a majority of the experiments with assistance from CL, L Wu, FL, RW and L Wang; LF and XD performed the IHC assay; YL and DZ conceived, designed, and performed bioinformatics analysis under supervision of KC; YY and QC wrote the paper; All authors discussed the results and commented on the manuscript.

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Correspondence to Kaifu Chen or Qi Cao.

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Yi, Y., Li, Y., Li, C. et al. Methylation-dependent and -independent roles of EZH2 synergize in CDCA8 activation in prostate cancer. Oncogene 41, 1610–1621 (2022). https://doi.org/10.1038/s41388-022-02208-x

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