Solid Tumour Target Discovery Group, Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Newcastle Upon Tyne, NE2 4HH, UK.
Nucleic Acids Res. 2013 Aug;41(14):6892-904. doi: 10.1093/nar/gkt469. Epub 2013 May 30.
The importance of the estrogen receptor (ER) in breast cancer (BCa) development makes it a prominent target for therapy. Current treatments, however, have limited effectiveness, and hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor superfamily of transcription factors that requires co-regulator proteins for complete regulation. Emerging evidence has implicated a small number of histone methyltransferase (HMT) and histone demethylase (HDM) enzymes as regulators of ER signalling, including the histone H3 lysine 9 tri-/di-methyl HDM enzyme KDM4B. Two recent independent reports have demonstrated that KDM4B is required for ER-mediated transcription and depletion of the enzyme attenuates BCa growth in vitro and in vivo. Here we show that KDM4B has an overarching regulatory role in the ER signalling cascade by controlling expression of the ER and FOXA1 genes, two critical components for maintenance of the estrogen-dependent phenotype. KDM4B interacts with the transcription factor GATA-3 in BCa cell lines and directly co-activates GATA-3 activity in reporter-based experiments. Moreover, we reveal that KDM4B recruitment and demethylation of repressive H3K9me3 marks within upstream regulatory regions of the ER gene permits binding of GATA-3 to drive receptor expression. Ultimately, our findings confirm the importance of KDM4B within the ER signalling cascade and as a potential therapeutic target for BCa treatment.
雌激素受体（ER）在乳腺癌（BCa）发展中的重要性使其成为治疗的重要靶点。然而，目前的治疗方法效果有限，因此定义新的治疗靶点至关重要。ER 是核激素受体超家族转录因子的成员，需要共调节蛋白才能完全调节。新出现的证据表明，少数组蛋白甲基转移酶（HMT）和组蛋白去甲基化酶（HDM）酶作为 ER 信号的调节剂，包括组蛋白 H3 赖氨酸 9 三/二甲基 HDM 酶 KDM4B。最近的两项独立研究表明，KDM4B 是 ER 介导的转录所必需的，并且该酶的耗竭会减弱体外和体内的 BCa 生长。在这里，我们表明 KDM4B 通过控制 ER 和 FOXA1 基因的表达在 ER 信号级联中具有全面的调节作用，这两个基因是维持雌激素依赖性表型的关键组成部分。KDM4B 在 BCa 细胞系中与转录因子 GATA-3 相互作用，并在基于报告基因的实验中直接共同激活 GATA-3 活性。此外，我们揭示了 KDM4B 在 ER 基因上游调节区域募集和去甲基化抑制性 H3K9me3 标记，允许 GATA-3 结合以驱动受体表达。最终，我们的研究结果证实了 KDM4B 在 ER 信号级联中的重要性以及作为 BCa 治疗的潜在治疗靶点。
