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Alterations of BRMS1-ARID4A Interaction Modify Gene Expression but Still Suppress Metastasis in Human Breast Cancer Cells

2008; Elsevier BV; Volume: 283; Issue: 12 Linguagem: Inglês

10.1074/jbc.m709446200

1083-351X

Douglas R. Hurst, Yi Xie, Kedar S. Vaidya, Alka Mehta, Blake P. Moore, Mary Ann Accavitti-Loper, Rajeev S. Samant, Ritu Saxena, Alexandra C. Silveira, Danny R. Welch,

Ferrocene Chemistry and Applications

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 ΔCC1 ) did not disrupt direct interaction in yeast two-hybrid screens but did prevent association by co-immunoprecipitation. These results suggest altered complex composition with BRMS1 mut . Although basal transcription repression was impaired and the pro-metastatic protein osteopontin was differentially down-regulated by BRMS1 L174D and BRMS1 ΔCC1 , both down-regulated the epidermal growth factor receptor and suppressed metastasis in MDA-MB-231 and -435 breast cancer xenograft models. We conclude that BRMS1 mut , 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.