Context: Enhancer of Zeste 2 (EZH2), a methyltransferase and an upregulated gene is an adverse prognosticator in prostate cancer. It catalyzes histone H3 lysine 27 trimethylation (H3K27me3) leading to repressive chromatin status (heterochromatin). Following demethylation and acetylation of H3 protein (H3K27ac) the result is transcriptionally activated status (euchromatin), a key metastasis facilitator being targeted by ongoing clinical trials, as with palbociclib. Here, we performed the first immunohistochemical study of H3K27ac expression in prostatic tissue and cancer metastasis, and determined a possible correlation with EZH2 expression.
Methods: Tissue microarrays were made and immunohistochemistry was performed for EZH2 and H3K27ac. Slides were scanned and image data utilized a software-assisted, unbiased quantification method. The software captured diaminobenzidine positive regions, and tissue areas.
Results: Benign prostate tissue expressed almost no EZH2 but showed strong H3K27-Ac positivity. Tumor was EZH2 positive (p < 0.05 vs. benign) with strongest staining in lymph node metastasis. H3K27-Ac was decreased in tumors, yet paradoxically had stagewise and gradewise progressive increases (both p < 0.05), with the strongest staining in lymph nodes. The overall relationship of EZH2 and H3K27ac was weakly correlated (r = 0.28, p < 0.05).
Conclusions: EZH2 and H3K27ac had an inverse correlation in benign versus (especially) low-grade and low-stage prostate cancers; however, in high-stage and high-grade cancers and metastases, H3K27ac increased significantly. Findings support EZH2 and H3K27ac as targets for cancer prevention in localized or low-grade prostate cancer, but we now note that their inverse relationship becomes uncoupled in advanced prostate cancer.
Keywords: EZH2; H3K27ac; Lymph node; Metastasis; Prostate cancer.
Copyright © 2022 Elsevier Inc. All rights reserved.