Introduction: Prostate cancer (PC) is characterized by dysregulated epigenetic signaling including altered levels of histone methylation and expression of histone methyltransferases (HMTs). Enhancer of Zeste Homolog 2 (EZH2) and nuclear receptor binding SET domain 2 (NSD2) are HMTs that tri-methylate H3K27 and di-methylate H3K36 respectively to regulate the transcriptional potential of genomic loci. These enzymes are upregulated in PC and represent putative drug targets. Here we investigate if these HMTs coregulate in tumors, and whether EZH2/NSD2 co-expression associates with cancer outcomes.
Methods: PC tissue microarrays (TMAs) constructed from benign, localized and metastatic PC tissue from 183 patients were analyzed, along with 142 cores from a castration resistant PC array. NSD2 and EZH2 protein levels were quantified with immunohistochemical staining using image analysis. Primary PC samples from The Cancer Genome Atlas (TCGA; n=498) and Memorial Sloan Kettering Cancer Center (MSKCC; n=150) were queried using cBioportal for cancer genomics. RNA-seq data was used to identify patients in the top quartile of NSD2 and EZH2 co-expression, who were compared to the remainder for Gleason Grade, tumor stage, and disease-free status.
Results: Analysis of TMA data shows the percentage of epithelial nuclei with NSD2/EZH2 co-expression was increased in CRPC compared to hormone sensitive PC (HSPC) tissues (p=0.02). Analysis of HSPC reveals an enrichment of co-expression in metastatic PC tissue relative to benign tissue (p<0.05). Histologic disease progression in primary tissue was associated with an increase in the proportion of patients from the top quartile of EZH2/NSD2 co-localization (p=0.01). Analysis of clinical data in the TCGA and MSKCC databases reveals a significantly higher proportion of patients in the top 25% of EZH2/NSD2 co-expression with Gleason scores 8-10 (p<0.001), with stage T4 and T3a/b tumors (p<0.01). This patient subset shows reduced disease-free survival at 60 months (p<0.01) (Figure 1).
Conclusions: Patients with robust EZH2/NSD2 co-expression are over-represented in CRPC TMAs, in patients with metastases, and in those with shorter disease-free survival. These results suggest that co-expression of these HMTs identify a more aggressive PC subtype and licenses them as a therapeutic target. Source of
