Frietze Seth, Lupien Mathieu, Silver Pamela A, Brown Myles
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
Cancer Res. 2008 Jan 1;68(1):301-6. doi: 10.1158/0008-5472.CAN-07-1983.
Estrogen receptor alpha (ER alpha) mediates breast cancer proliferation through transcriptional mechanisms involving the recruitment of specific coregulator complexes to the promoters of cell cycle genes. The coactivator-associated arginine methyltransferase CARM1 is a positive regulator of ER alpha-mediated transcriptional activation. Here, we show that CARM1 is essential for estrogen-induced cell cycle progression in the MCF-7 breast cancer cell line. CARM1 is specifically required for the estrogen-induced expression of the critical cell cycle transcriptional regulator E2F1 whereas estrogen stimulation of cyclin D1 is CARM1 independent. Upon estrogen stimulation, the E2F1 promoter is subject to CARM1-dependent dimethylation on histone H3 arginine 17 (H3R17me2) in a process that parallels the recruitment of ER alpha. Additionally, we find that the recruitment of CARM1 and subsequent histone arginine dimethylation are dependent on the presence of the oncogenic coactivator AIB1. Thus, CARM1 is a critical factor in the pathway of estrogen-stimulated breast cancer growth downstream of ER alpha and AIB1 and upstream of the cell cycle regulatory transcription factor E2F1. These studies identify CARM1 as a potential new target in the treatment of estrogen-dependent breast cancer.
雌激素受体α（ERα）通过转录机制介导乳腺癌增殖，该机制涉及将特定的共调节因子复合物募集到细胞周期基因的启动子上。共激活因子相关的精氨酸甲基转移酶CARM1是ERα介导的转录激活的正调节因子。在此，我们表明CARM1对于MCF-7乳腺癌细胞系中雌激素诱导的细胞周期进程至关重要。雌激素诱导关键细胞周期转录调节因子E2F1的表达特别需要CARM1，而细胞周期蛋白D1的雌激素刺激则不依赖于CARM1。雌激素刺激后，E2F1启动子在组蛋白H3精氨酸17（H3R17me2）上发生依赖于CARM1的二甲基化，这一过程与ERα的募集平行。此外，我们发现CARM1的募集及随后的组蛋白精氨酸二甲基化依赖于致癌共激活因子AIB1的存在。因此，CARM1是雌激素刺激的乳腺癌生长途径中ERα和AIB1下游以及细胞周期调节转录因子E2F1上游的关键因子。这些研究将CARM1确定为雌激素依赖性乳腺癌治疗中的潜在新靶点。
