Tandem histone methyltransferase upregulation defines a unique aggressive prostate cancer phenotype
Menée à partir d'échantillons tumoraux issus de patients atteints d'un cancer de la prostate hormonosensible et résistant à la castration et menée à l'aide de données du projet "The Cancer Genome Atlas", du "Memorial Sloan Kettering Cancer Center" et du "Stand Up to Cancer/Prostate Cancer Foundation", cette étude met en évidence une association entre la co-expression des méthyltransférases EZH2 et NSD2 et le caractère agressif de la maladie
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.
British Journal of Cancer , résumé, 2021