EZH2 Represent Therapeutic Strategy for Prostate Cancer Prevention
MetadataShow full item record
Background: Prostate cancer (PCa) has been proposed as a model for “epigenomic catastrophe”, due to numerous changes in DNA methylation patterns and histone modifications that can be detected pre-carcinogenesis. Moreover, studies show that increased expression of the histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) occurs as a pre-neoplastic event in mouse and human samples representing prostatic intraepithelial neoplasia (PIN). EZH2 is the catalytic subunit of polycomb repressive complex 2 and is responsible for global repression of genes via tri-methylation on histone 3 lysine 27 (H3K27me3). These early epigenetic alterations in the form of DNA methylation and histone modification can predispose cells to the genetic abnormalities that can advance neoplastic progression. The findings that epigenetic changes can be found so early in tumorigenesis of PCa makes epigenetic therapies, such as inhibitors of EZH2, an attractive strategy for PCa prevention. In the light of above given background information, we hypothesize that EZH2 is required for progression of pre-cancerous lesion in PCa and inhibition of EZH2 at pre-cancerous stage decreases progression of pre-cancerous lesion. Method: Gene Set Enrichment Analysis (GSEA) was performed for in silico analysis of gene expression profiles of published datasets from prostate mouse models with PIN. DZNep, GSK126 and EPZ6438 inhibitors were used to assess the effects of pharmacological inhibition of EZH2 on proliferation, cell cycle distribution, clonogenicity and senescence in-vitro models of PCa. To assess EZH2 methyltransferase dependency for PCa progression in-vivo , Hi-Myc transgenic mice were treated with the EZH2 inhibitors, DZNep or EPZ0011989. Histological assessment by H&E and IHC was performed to investigate the effect of EZH2 methyltransferase loss during PCa initiation. Results: Our results demonstrated that EZH2 and its catalytic mark H3K27me3 are highly expressed in PIN lesions from the Hi-Myc mouse model of PCa. GSEA of transgenic mouse models with PIN were positively enriched for EZH2 associated datasets. EZH2 expression and activity were increased before transformation in isogenic progressive models. Moreover, pharmacological inhibition of EZH2 activity induced G2-M and S phase arrest in PrEC-AR-c-Myc model. Further evaluation of pharmacological inhibition of EZH2 in-vitro showed significantly decreased clonogenicity and increased senescence. Evaluation of pharmacological inhibition of EZH2 in-vivo showed marked reduction in overall genitourinary and prostate weights compared to vehicle treated mice. Treatment with inhibitors of EZH2 was further associated with delayed progression in Ventral, Lateral, and Dorsal lobes in the Hi-Myc model. IHC evaluation showed significant reduction in H3K27me3 levels and proliferation within prostate lobes. Conclusion: Our data demonstrates that deregulation of EZH2 plays important role in progression of PIN lesions and can be targeted in prevention strategies. Further, EZH2 is highly expressed during PIN and EZH2 associated molecular signatures select for PIN lesions that progress to adenocarcinoma. Inhibition of EZH2 leads to cell cycle arrest and senescence. Overall, our results demonstrate that targeting EZH2 as a prostate cancer prevention strategy is a viable option and inhibition of EZH2 decreases proliferation and delays progression.