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Genetics and Genomics

Tandem histone methyltransferase upregulation defines a unique aggressive prostate cancer phenotype



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).


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.


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).


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


  1. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).

  2. Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481–492 (2011).

    Article  CAS  Google Scholar 

  3. Kouzarides, T. SnapShot: histone-modifying enzymes. Cell 128, 802.e1–02.e2 (2007).

    Article  Google Scholar 

  4. Xu, K., Wu, Z. J., Groner, A. C., He, H. H., Cai, C., Lis, R. T. et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science 338, 1465–1469 (2012).

    Article  CAS  Google Scholar 

  5. Varambally, S., Dhanasekaran, S. M., Zhou, M., Barrette, T. R., Kumar-Sinha, C., Sanda, M. G. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  Google Scholar 

  6. Asangani, I. A., Ateeq, B., Cao, Q., Dodson, L., Pandhi, M., Kunju, L. P. et al. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol. Cell 49, 80–93 (2013).

    Article  CAS  Google Scholar 

  7. Friedman, J. M., Jones, P. A. & Liang, G. The tumor suppressor microRNA-101 becomes an epigenetic player by targeting the polycomb group protein EZH2 in cancer. Cell Cycle 8, 2313–2314 (2009).

  8. Varambally, S., Cao, Q., Mani, R. S., Shankar, S., Wang, X., Ateeq, B. et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695–1699 (2008).

    Article  CAS  Google Scholar 

  9. Nikoloski, G., Langemeijer, S. M., Kuiper, R. P., Knops, R., Massop, M., Tonnissen, E. R. et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat. Genet. 42, 665–667 (2010).

    Article  CAS  Google Scholar 

  10. Popovic, R., Martinez-Garcia, E., Giannopoulou, E. G., Zhang, Q., Ezponda, T., Shah, M. Y. et al. Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation. PLoS Genet. 10, e1004566 (2014).

    Article  Google Scholar 

  11. Li, J., Ahn, J. H. & Wang, G. G. Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol. Life Sci. 76, 2899–2916 (2019).

    Article  CAS  Google Scholar 

  12. Nimura, K., Ura, K., Shiratori, H., Ikawa, M., Okabe, M., Schwartz, R. J. et al. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 460, 287–291 (2009).

    Article  CAS  Google Scholar 

  13. Barski, A., Cuddapah, S., Cui, K., Roh, T. Y., Schones, D. E., Wang, Z. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).

    Article  CAS  Google Scholar 

  14. Wang, G., Zhao, D., Spring, D. J. & DePinho, R. A. Genetics and biology of prostate cancer. Genes Dev. 32, 1105–1140 (2018).

    Article  CAS  Google Scholar 

  15. Damodaran, S., Damaschke, N., Gawdzik, J., Yang, B., Shi, C., Allen, G. O. et al. Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes. BMC Cancer 17, 874 (2017).

    Article  Google Scholar 

  16. Lee, J. H., Yang, B., Lindahl, A. J., Damaschke, N., Boersma, M. D., Huang, W. et al. Identifying dysregulated epigenetic enzyme activity in castrate-resistant prostate cancer development. ACS Chem. Biol. 12, 2804–2814 (2017).

    Article  CAS  Google Scholar 

  17. Desmeules, P., Hovington, H., Nguile-Makao, M., Leger, C., Caron, A., Lacombe, L. et al. Comparison of digital image analysis and visual scoring of KI-67 in prostate cancer prognosis after prostatectomy. Diagn. Pathol. 10, 67 (2015).

    Article  Google Scholar 

  18. Taylor, B. S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    Article  CAS  Google Scholar 

  19. Liu, J., Lichtenberg, T., Hoadley, K. A., Poisson, L. M., Lazar, A. J., Cherniack, A. D. et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell 173, 400–16.e11 (2018).

    Article  CAS  Google Scholar 

  20. Abida, W., Cyrta, J., Heller, G., Prandi, D., Armenia, J., Coleman, I. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl Acad. Sci. USA 116, 11428–11436 (2019).

    Article  CAS  Google Scholar 

  21. Aytes, A., Giacobbe, A., Mitrofanova, A., Ruggero, K., Cyrta, J., Arriaga, J. et al. NSD2 is a conserved driver of metastatic prostate cancer progression. Nat. Commun. 9, 5201 (2018).

    Article  Google Scholar 

  22. Kang, H. B., Choi, Y., Lee, J. M., Choi, K. C., Kim, H. C., Yoo, J. Y. et al. The histone methyltransferase, NSD2, enhances androgen receptor-mediated transcription. FEBS Lett. 583, 1880–1886 (2009).

    Article  CAS  Google Scholar 

  23. Zhang, Y., Zheng, D., Zhou, T., Song, H., Hulsurkar, M., Su, N. et al. Androgen deprivation promotes neuroendocrine differentiation and angiogenesis through CREB-EZH2-TSP1 pathway in prostate cancers. Nat. Commun. 9, 4080 (2018).

    Article  Google Scholar 

  24. Bachmann, I. M., Halvorsen, O. J., Collett, K., Stefansson, I. M., Straume, O., Haukaas, S. A. et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol. 24, 268–273 (2006).

    Article  CAS  Google Scholar 

  25. Saramäki, O. R., Tammela, T. L., Martikainen, P. M., Vessella, R. L. & Visakorpi, T. The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancer. Genes Chromosomes Cancer 45, 639–645 (2006).

    Article  Google Scholar 

  26. Tian, X., Tao, F., Zhang, B., Dong, J. T. & Zhang, Z. The miR-203/SNAI2 axis regulates prostate tumor growth, migration, angiogenesis and stemness potentially by modulating GSK-3β/β-CATENIN signal pathway. IUBMB Life 70, 224–236 (2018).

    Article  CAS  Google Scholar 

  27. Saini, S., Majid, S., Yamamura, S., Tabatabai, L., Suh, S. O., Shahryari, V. et al. Regulatory role of mir-203 in prostate cancer progression and metastasis. Clin. Cancer Res. 17, 5287–5298 (2011).

    Article  CAS  Google Scholar 

  28. Taplin, M.-E., Hussain, A., Shah, S., Shore, N. D., Agrawal, M., Clark, W. et al. ProSTAR: a phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 37(Suppl.), TPS335–TPS335 (2019).

    Article  Google Scholar 

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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



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.

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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).

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