CARM1 Regulates Estrogen-Stimulated Breast Cancer Growth through Up-regulation of E2F1

Abstract

Estrogen receptor A (ERA) 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 ERAmediated 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 ERA. 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 ERA 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. [Cancer Res 2008;68(1):301-6]

The prognostic significance of PELP1 expression in invasive breast cancer with emphasis on the ER-positive luminal-like subtype

“…In this study, we found a significant positive correlation between PELP1 and CRAM1 which is necessary for the E2-induced proliferation of breast cancer cells via E2F1 and its target genes [26,27]. This positive correlation at the protein level suggests a possible synergistic action between PELP1 and CARM1, being both ER coactivators, in E2-induced proliferation of ER-positive breast cancer cells.…”

Identification of a Novel Inhibitor of Coactivator-associated Arginine Methyltransferase 1 (CARM1)-mediated Methylation of Histone H3 Arg-17

“…The arginine methyltransferase, CARM1/PRMT4, has been shown to regulate important cellular processes such as pluripotency maintenance (16,32), differentiation (6,15,17), splicing (18), and transcriptional activation (10 -14), as well as tumor manifestation and progression (33,34). However, the methyltransferase activity of this coactivator has been linked with only a few cases of transcriptional activation, muscle and thymocyte differentiation, and tumor progression.…”

In situ histone landscape of nephrogenesis

“…[35][36][37] H3R17me2as is generally an activating mark. 38,39 Interestingly, there was a differential enrichment of these three histone marks, since H3R2me2 and H3R17me2 are abundantly expressed in the cap mesenchyme and nascent nephrons, whereas H3R8me2 is more enriched in nascent nephrons (Fig. 10A-C).…”