Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Int J Oncol. 2012 Nov;41(5):1701-6. doi: 10.3892/ijo.2012.1618. Epub 2012 Sep 4.
Estrogen receptor α (ERα) plays a pivotal role in the genesis of the majority of breast tumors. Consequently, endocrine therapy is now routinely utilized in the clinic for the treatment of ERα-positive breast cancer patients. However, how ERα activity becomes dysregulated in breast cancer cells remains to be elucidated. The aim of this study was to show that the histone demethylase JMJD2A, also known as KDM4A, is capable of forming a complex with ERα in vivo. Moreover, wild-type JMJD2A, but not a catalytically impaired mutant, was able to strongly coactivate ERα-mediated transcription. Consistently, the downregulation of JMJD2A in human T47D breast cancer cells led to a decreased expression of cyclin D1, a prominent ERα target gene and cell cycle regulator. The downregulation of JMJD2A induced a reduction in the growth of T47D cells. In addition, we found that JMJD2A is overexpressed in human breast tumors both at the mRNA and protein level. Taken together, these data indicate that the overexpression of JMJD2A may contribute to breast tumor formation by stimulating ERα activity and that JMJD2A may be a breast-relevant oncoprotein. As such, small molecule drugs targeting the catalytic center of JMJD2A might be useful in breast cancer adjuvant therapy.
雌激素受体α（ERα）在大多数乳腺癌的发生中起着关键作用。因此，内分泌治疗现在已在临床上常规用于治疗 ERα阳性乳腺癌患者。然而，ERα 活性在乳腺癌细胞中如何失调仍有待阐明。本研究旨在表明组蛋白去甲基化酶 JMJD2A（也称为 KDM4A）能够在体内与 ERα 形成复合物。此外，野生型 JMJD2A，但不是催化缺陷突变体，能够强烈协同激活 ERα 介导的转录。一致地，JMJD2A 在人 T47D 乳腺癌细胞中的下调导致细胞周期调节因子和 ERα 主要靶基因 cyclin D1 的表达减少。JMJD2A 的下调导致 T47D 细胞的生长减少。此外，我们发现 JMJD2A 在人乳腺癌肿瘤中无论是在 mRNA 还是蛋白水平都过度表达。总之，这些数据表明 JMJD2A 的过表达可能通过刺激 ERα 活性导致乳腺癌的形成，并且 JMJD2A 可能是一种与乳房相关的致癌蛋白。因此，针对 JMJD2A 催化中心的小分子药物可能对乳腺癌辅助治疗有用。
