Department of Urology, Case Western Reserve University, Cleveland, Ohio.
The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio.
Mol Carcinog. 2020 Aug;59(8):955-966. doi: 10.1002/mc.23214. Epub 2020 May 11.
Maspin repression is frequently observed in prostate cancer; however, the molecular mechanism(s) causing the loss is not completely understood. Here, we demonstrate that inhibition of class I histone deacetylases (HDACs) mediates re-expression of maspin which plays an essential role in suppressing proliferation and migration capability in prostate cancer cells. Human prostate cancer LNCaP and DU145 cells treated with HDAC inhibitors, sodium butyrate, and trichostatin A, resulted in maspin re-expression. Interestingly, an exploration into the molecular mechanisms demonstrates that maspin repression in prostate tumor and human prostate cancer cell lines occurs via epigenetic silencing through an increase in HDAC activity/expression, independent of promoter DNA hypermethylation. Furthermore, transcriptional activation of maspin was accompanied with the suppression of HDAC1 and HDAC8 with significant p53 enrichment at the maspin promoter associated with an increase in histone H3/H4 acetylation. Our results provide evidence of maspin induction as a critical epigenetic event altered by class I HDACs in the restoration of balance to delay proliferation and migration ability of prostate cancer cells.
Maspin 的表达抑制在前列腺癌中经常观察到；然而，导致这种缺失的分子机制尚不完全清楚。在这里，我们证明了 I 类组蛋白去乙酰化酶 (HDACs) 的抑制介导了 maspin 的重新表达，maspin 在抑制前列腺癌细胞的增殖和迁移能力方面起着至关重要的作用。用 HDAC 抑制剂、丁酸钠和曲古抑菌素 A 处理人前列腺癌细胞 LNCaP 和 DU145，导致 maspin 的重新表达。有趣的是，对分子机制的探索表明，前列腺肿瘤和人前列腺癌细胞系中的 maspin 抑制是通过 HDAC 活性/表达的增加通过表观遗传沉默发生的，与启动子 DNA 超甲基化无关。此外，maspin 的转录激活伴随着 HDAC1 和 HDAC8 的抑制，maspin 启动子处的 p53 丰度显著增加，与组蛋白 H3/H4 乙酰化增加有关。我们的结果提供了证据，证明 maspin 的诱导是由 I 类 HDACs 改变的关键表观遗传事件，可恢复平衡，延缓前列腺癌细胞的增殖和迁移能力。
