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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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.
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.
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.
The authors declare no competing interests.
This work was supported by the Department of Defense Grant-DODPCRP W81XWH (to D.J.).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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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