Alterations of BRMS1-ARID4A interaction modify gene expression but still suppress metastasis in human breast cancer cells

作者：Hurst Douglas R; Xie Yi; Vaidya Kedar S; Mehta Alka; Moore Blake P; Accavitti Loper Mary Ann; Samant Rajeev S; Saxena Ritu; Silveira Alexandra C; Welch Danny R^*

来源：Journal of Biological Chemistry, 2008, 283(12): 7438-7444.

DOI：10.1074/jbc.M709446200

The BRMS1 metastasis suppressor interacts with the protein AT-rich interactive domain 4A ( ARID4A, RBBP1) as part of SIN3.histone deacetylase chromatin remodeling complexes. These transcriptional co-repressors regulate diverse cell phenotypes depending upon complex composition. To define BRMS1 complexes and their roles in metastasis suppression, we generated BRMS1 mutants ( BRMS1(mut)) and mapped ARID4A interactions. BRMS1(L174D) disrupted direct interaction with ARID4A in yeast two-hybrid genetic screens but retained an indirect association with ARID4A in MDA-MB-231 and - 435 human breast cancer cell lines by co-immunoprecipitation. Deletion of the first coiled-coil domain ( BRMS1(Delta CC1)) did not disrupt direct interaction in yeast two-hybrid screens but did prevent association by co-immunoprecipitation. These results suggest altered complex composition with BRMS1mut. Although basal transcription repression was impaired and the pro-metastatic protein osteopontin was differentially down-regulated by BRMS1(L174D) and BRMS1(Delta CC1), both down-regulated the epidermal growth factor receptor and suppressed metastasis in MDA-MB-231 and - 435 breast cancer xenograft models. We conclude that BRMS1mut, which modifies the composition of a SIN3.histone deacetylase chromatin remodeling complex, leads to altered gene expression profiles. Because metastasis requires the coordinate expression of multiple genes, down-regulation of at least one important gene, such as the epidermal growth factor receptor, had the ability to suppress metastasis. Understanding which interactions are necessary for particular biochemical/ cellular functions may prove important for future strategies targeting metastasis.

• 出版日期2008-3-21