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Genetics and Genomics

Tandem histone methyltransferase upregulation defines a unique aggressive prostate cancer phenotype

British Journal of Cancer volume 125, pages 247–254 (2021)Cite this article

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Abstract

Background

Histone modifications alter transcriptional gene function and participate in cancer progression. Enhancer-of-Zeste-Homologue-2 (EZH2) and Nuclear-Receptor-Binding-SET-domain2 (NSD2) methylate H3K27 and H3K36, respectively, to regulate transcription. Given the therapeutic interest in these enzymes, we investigated expression and coregulation in hormone-sensitive (HS) and castrate-resistant (CR) prostate cancer (PC).

Methods

EZH2 and NSD2 levels were quantified using VECTRA analysis in HS and CRPC tissue microarrays (n = 105 + 66). Expression data from The Cancer Genome Atlas (n = 498), Memorial Sloan Kettering Cancer Center (n = 240), and Stand Up to Cancer/Prostate Cancer Foundation (n = 444) cBioportal datasets were queried, and associations between EZH2 and NSD2 and clinicopathologic variables determined.

Results

Tumour expression of NSD2, but not EZH2, increased in CRPC (p = 0.05, 0.09). Epithelial nuclei co-expressing NSD2 and EZH2 increased in CRPC compared to HSPC (69 vs 42%, p = 0.02), and in metastatic tissue relative to benign (55 vs 35%, p = 0.02). cBioportal analysis revealed collinear NSD2/EZH2 expression (Spearman = 0.57, 0.58, 0.58, all p < 0.001). NSD2/EZH2 co-expression significantly associates with clinicopathologic characteristics including grade group, stage and seminal vesicle involvement. On univariate and multivariate analysis tumours co-expressing NSD2 and EZH2 conferred increased risk of recurrence (hazard ratio: 2.6, 95% confidence inerval: 1.2–5.4, p = 0.01). Kaplan–Meier analysis revealed reduced progression-free-survival of NSD2 and EZH2 co-expression patients in datasets (p < 0.001, 0.002).

Conclusions

Increased EZH2/NSD2 co-expression is overrepresented in CRPC, metastases and associates with shorter disease-free survival in PC patients. Coregulation of these two histone methyltransferases is a biomarker for aggressive PC and licenses them as therapeutic targets.

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Fig. 1: Concurrent immunostaining demonstrates the percentage of cells with colocalisation of NSD2 and EZH2 significantly increases in castrate-resistant prostate cancer (CRPC) compared to hormone-sensitive disease.
Fig. 2: Core immunostaining of hormone-sensitive prostate cancer (HSPC) demonstrates NSD2 increases during prostate cancer progression and co-expression increases in metastases.
Fig. 3: Prostate cancer database expression data and patient microarray staining demonstrate significant EZH2 and NSD2 correlation within individual tumours and NSD2 and EZH2 expression predicts biochemical recurrence in PC

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Acknowledgements

We thank the University of Wisconsin Translational Research Initiatives in Pathology laboratory (TRIP), supported by the UW Department of Pathology and Laboratory Medicine, UWCCC (P30 CA014520) and the Office of the Director-NIH (S10OD023526) for use of its facilities and services.

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Authors and Affiliations

  1. Department of Urology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA

    Mikolaj Filon, Joseph Gawdzik, Andrew Truong, Glenn Allen, Tariq Khemees, Rehaan Machhi, Bing Yang & David Jarrard

  2. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Wei Huang

  3. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI, USA

    Peter Lewis, John Denu & David Jarrard

  4. Department of Biomolecular Chemistry, University of Wisconsin, Madison, WI, USA

    Peter Lewis & John Denu

  5. Wisconsin Institute for Discovery and the Morgridge Institute for Research, University of Wisconsin, Madison, WI, USA

    Peter Lewis & John Denu

  6. Molecular and Environmental Toxicology Program, University of Wisconsin, Madison, WI, USA

    David Jarrard

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Contributions

M.F. organised and interpreted raw data, performed the statistical analysis, designed figures and tables and drafted the manuscript. J.G. was instrumental in designing the experiment and performing data compilation and analysis. A.T. compiled and organised raw data including statistical analysis. G.A. provided statistical analysis and data organisation. W.H. read the H&E slides and was involved in idea development, data development and review, and editing. T.K. provided analysis of raw results and assistance with figures and data presentation. R.M. compiled and analysed raw data involving the tissue staining results. P.L. assisted in idea development, data development and review, and editing of the manuscript. B.Y. assisted in statistical analysis and construction of figures. J.D. was involved in idea development, data development and editing. D.J. designed and supervised the study, interpreted data and edited the manuscript.

Corresponding author

Correspondence to David Jarrard.

Ethics declarations

Ethics approval and consent to participate

Individual medical centres obtained institutional review board approval exemption or waiver for the use of archived clinical samples for research purposes. This study was performed in accordance with the Declaration of Helsinki. Data and outcomes for cBioportal are made through a data-sharing agreement. Approvals and patient consents were obtained through the University of Wisconsin Carbone Cancer Center Tissue Biobank (IRB #2016-0934) and through the University of Wisconsin Institutional Review Board IRB# XPO5338.

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary information files. RNA expression data from the TCGA, MSKCC and SU2C/PCF is available publicly online from the cBioPortal for cancer genomics.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by the Department of Defense Grant-DODPCRP W81XWH (to D.J.).

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Filon, M., Gawdzik, J., Truong, A. et al. Tandem histone methyltransferase upregulation defines a unique aggressive prostate cancer phenotype. Br J Cancer 125, 247–254 (2021). https://doi.org/10.1038/s41416-021-01398-7

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