BRG1 Activates Proliferation and Transcription of Cell Cycle-Dependent Genes in Breast Cancer Cells

Abstract

Cancer malignancy is usually characterized by unlimited self-renewal. In some types of advanced tumors that are rapidly dividing, gene expression profiles depict elevations in pro-proliferative genes accompanied by coordinately elevated transcription of factors responsible for removal of DNA lesions. In our studies, fast proliferating breast cancer cell lines (MDA-MB-231 and MCF7), BRG1, a component of the SWI/SNF complex, emerges as an activator of functionally-linked genes responsible for activities such as mitotic cell divisions and DNA repair. Products of at least some of them are considerably overrepresented in breast cancer cells and BRG1 facilitates growth of MCF7 and MDA-MB-231 cell lines. BRG1 occurs at the promoters of genes such as CDK4, LIG1, and NEIL3, which are transcriptionally controlled by cell cycle progression and highly acetylated by EP300 in proliferating cells. As previously documented, in dividing cells BRG1 directly activates gene transcription by evicting EP300 modified nucleosomes from the promoters and, thereby, relaxing chromatin. However, the deficiency of BRG1 or EP300 activity for 48 h leads to cell growth arrest and to chromatin compaction, but also to the assembly of RB1/HDAC1/EZH2 complexes at the studied cell cycle-dependent gene promoters. Epigenetic changes include histone deacetylation and accumulation of H3K27me trimethylation, both known to repress transcription. Cell cycle arrest in G1 by inhibition of CDK4/6 phenocopies the effect of the long-term BRG1 inhibition on the chromatin structure. These results suggest that BRG1 may control gene transcription also by promoting expression of genes responsible for cell cycle progression in the studied breast cancer cells. In the current study, we show that BRG1 binding occurs at the promoters of functionally linked genes in proliferating breast cancer cells, revealing a new mechanism by which BRG1 defines gene transcription.

Keywords

• brg1 (brahma-related gene 1)
• ep300 (e1a binding protein p300)
• gene transcription
• breast cancer epigenetics