From the Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
J Biol Chem. 2013 Sep 13;288(37):26731-40. doi: 10.1074/jbc.M113.483958. Epub 2013 Aug 2.
The KLF5 (Krüppel-like factor 5) transcription factor is specifically expressed in a subset of estrogen receptor α-negative breast cancers. Although KLF5 promotes breast cancer cell cycle progression, survival, and tumorigenesis, the mechanism by which KLF5 promotes breast cancer is still not entirely understood. Here, we demonstrate that mPGES1, encoding microsomal prostaglandin E2 synthase 1 (mPGES1), is a KLF5 direct downstream target gene. KLF5 overexpression or knockdown positively altered the levels of mPGES1 mRNA and protein in multiple breast cell lines. 12-O-Tetradecanoylphorbol-13-acetate induced the expression of both KLF5 and mPGES1 in dosage- and time-dependent manners. The induction of KLF5 was essential for 12-O-tetradecanoylphorbol-13-acetate to induce mPGES1 expression. Additionally, KLF5 bound to the mPGES1 gene proximal promoter and activated its transcription. Both KLF5 and mPGES1 promoted prostaglandin E2 production; regulated p21, p27, and Survivin downstream gene expression; and likewise stimulated cell proliferation. Overexpression of mPGES1 partially rescued the KLF5 knockdown-induced downstream gene expression changes and growth arrest in MCF10A cells. Finally, we demonstrate that the expression of mPGES1 was positively correlated with the estrogen receptor α/progesterone receptor/HER2 triple-negative status. These findings suggest that mPGES1 is a target gene of KLF5, making it a new biomarker and a potential therapeutic target for triple-negative breast cancers.
KLF5（Krüppel 样因子 5）转录因子特异性表达于雌激素受体α阴性乳腺癌的一个亚群中。尽管 KLF5 促进乳腺癌细胞周期进程、存活和肿瘤发生，但 KLF5 促进乳腺癌的机制仍不完全清楚。在这里，我们证明编码微粒体前列腺素 E2 合酶 1（mPGES1）的 mPGES1 是 KLF5 的直接下游靶基因。KLF5 的过表达或敲低以剂量和时间依赖的方式改变了多种乳腺细胞系中 mPGES1 mRNA 和蛋白的水平。12-O-十四烷酰佛波醇 13-乙酸酯以剂量和时间依赖的方式诱导 KLF5 和 mPGES1 的表达。KLF5 的诱导对于 12-O-十四烷酰佛波醇 13-乙酸酯诱导 mPGES1 表达是必需的。此外，KLF5 结合到 mPGES1 基因近端启动子并激活其转录。KLF5 和 mPGES1 均促进前列腺素 E2 的产生；调节 p21、p27 和 Survivin 下游基因表达；并同样刺激细胞增殖。mPGES1 的过表达部分挽救了 MCF10A 细胞中 KLF5 敲低诱导的下游基因表达变化和生长阻滞。最后，我们证明 mPGES1 的表达与雌激素受体α/孕激素受体/HER2 三阴性状态呈正相关。这些发现表明 mPGES1 是 KLF5 的靶基因，使其成为三阴性乳腺癌的新生物标志物和潜在治疗靶点。
