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

Academic Article


  • 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 ) and mapped ARID4A interactions. BRMS1 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 ) 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 . Although basal transcription repression was impaired and the pro-metastatic protein osteopontin was differentially down-regulated by BRMS1 and BRMS1 , 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 , 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. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc. mut L174D ΔCC1 mut L174D ΔCC1 mut
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    Author List

  • Hurst DR; Xie Y; Vaidya KS; Mehta A; Moore BP; Accavitti-Loper MA; Samant RS; Saxena R; Silveira AC; Welch DR
  • Start Page

  • 7438
  • End Page

  • 7444
  • Volume

  • 283
  • Issue

  • 12