The Wistar Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania, Philadelphia, PA 19104, USA.
Mol Cancer Res. 2013 Apr;11(4):360-9. doi: 10.1158/1541-7786.MCR-12-0661. Epub 2013 Jan 29.
Epithelial ovarian cancer (EOC) accounts for the most gynecologic malignancy-associated deaths in the United States. Enhancer of zeste homolog 2 (EZH2), which silences gene expression through generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3), is often overexpressed in EOCs and has been suggested as a therapeutic target. However, the mechanism underlying EZH2 overexpression in EOCs is unknown. Here, we show that EZH2 is upregulated at the transcription level, and two CCAAT boxes in the proximal regions of the human EZH2 gene promoter are critical for its transcription in EOC cells. Indeed, NF-YA, the regulatory subunit of the CCAAT-binding transcription factor NF-Y, is expressed at higher levels in human EOCs than in primary human ovarian surface epithelial (HOSE) cells. In addition, there is a positive correlation between expression of NF-YA and EZH2 in EOCs. Notably, high NF-YA expression predicts shorter overall survival in patients with EOCs. The association of NF-YA with the promoter of the human EZH2 gene is enhanced in human EOC cells compared with primary HOSE cells. Significantly, knockdown of NF-YA downregulates EZH2, decreases H3K27Me3 levels, and suppresses the growth of human EOC cells both in vitro and in a xenograft mouse model. Notably, NF-YA knockdown induces apoptosis of EOC cells and ectopic EZH2 expression partially rescues apoptosis induced by NF-YA knockdown. Together, these data reveal that NF-Y is a key regulator of EZH2 expression and is required for EOC cell proliferation, thus representing a novel target for developing EOC therapeutics.
上皮性卵巢癌（EOC）是美国妇科恶性肿瘤相关死亡的主要原因。EZH2 通过在组蛋白 H3 的赖氨酸 27 位上产生三甲基化来沉默基因表达，在 EOC 中常过表达，并被认为是一个治疗靶点。然而，EOC 中 EZH2 过表达的机制尚不清楚。在这里，我们表明 EZH2 在转录水平上调，并且人 EZH2 基因启动子近端区域的两个 CCAAT 盒对于 EOC 细胞中的转录至关重要。事实上，CCAAT 结合转录因子 NF-Y 的调节亚基 NF-YA 在人 EOC 中的表达水平高于原代人卵巢表面上皮（HOSE）细胞。此外，NF-YA 和 EZH2 在 EOC 中的表达之间存在正相关。值得注意的是，NF-YA 高表达预示着 EOC 患者总生存期较短。与原代 HOSE 细胞相比，NF-YA 与人 EZH2 基因启动子的结合在人 EOC 细胞中增强。显著地，NF-YA 的敲低下调 EZH2，降低 H3K27Me3 水平，并抑制体外和异种移植小鼠模型中人 EOC 细胞的生长。值得注意的是，NF-YA 敲低诱导 EOC 细胞凋亡，而 EZH2 的异位表达部分挽救了 NF-YA 敲低诱导的凋亡。总之，这些数据表明 NF-Y 是 EZH2 表达的关键调节剂，是 EOC 细胞增殖所必需的，因此代表了开发 EOC 治疗方法的新靶点。
