The Institute of Genetics and Cytology, Northeast Normal University, Changchun, China.
PLoS One. 2012;7(7):e40943. doi: 10.1371/journal.pone.0040943. Epub 2012 Jul 13.
All-trans retinoic acid (ATRA) has been widely investigated for treatments of many cancers including prostate cancer. HOXB13, silenced in androgen receptor-negative (AR(-)) prostate cancer cells, plays a role in AR(-) prostate cancer cell growth arrest. In this study we intended to elucidate the mechanisms that are involved in the proliferation inhibition of AR(-) prostate cancer cells triggered by ATRA. We discovered that ATRA was able to induce the growth arrest and to increase HOXB13 expression in AR(-) prostate cancer cells. Both EZH2 and DNMT3b participated in the repression of HOXB13 expression through an epigenetic mechanism involving DNA and histone methylation modifications. Specifically, EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. Moreover, ATRA could upregulate HOXB13 through decreasing EZH2 and DNMT3b expressions and reducing their interactions with the HOXB13 promoter. Concurrently, the methylation level of the HOXB13 promoter was reduced upon the treatment of ATRA. Results from this study implicated a novel effect of ATRA in inhibition of the growth of AR(-) resistant human prostate cancer cells through alteration of HOXB13 expression as a result of epigenetic modifications.
全反式维甲酸（ATRA）已被广泛研究用于治疗包括前列腺癌在内的多种癌症。HOXB13 在雄激素受体阴性（AR(-)）前列腺癌细胞中沉默，在 AR(-)前列腺癌细胞生长抑制中发挥作用。在这项研究中，我们旨在阐明 ATRA 触发 AR(-)前列腺癌细胞增殖抑制所涉及的机制。我们发现 ATRA 能够诱导 AR(-)前列腺癌细胞的生长停滞并增加 HOXB13 的表达。EZH2 和 DNMT3b 通过涉及 DNA 和组蛋白甲基化修饰的表观遗传机制参与 HOXB13 表达的抑制。具体而言，EZH2 募集 DNMT3b 到 HOXB13 启动子上形成抑制复合物。此外，ATRA 可以通过降低 EZH2 和 DNMT3b 的表达并减少它们与 HOXB13 启动子的相互作用来上调 HOXB13。同时，ATRA 处理后 HOXB13 启动子的甲基化水平降低。这项研究的结果表明，ATRA 通过表观遗传修饰改变 HOXB13 的表达来抑制 AR(-)耐药人前列腺癌细胞的生长，从而产生一种新的作用。
