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PMID:17000776

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Citation

Liu, Y, Smith, PW and Jones, DR (2006) Breast cancer metastasis suppressor 1 functions as a corepressor by enhancing histone deacetylase 1-mediated deacetylation of RelA/p65 and promoting apoptosis. Mol. Cell. Biol. 26:8683-96

Abstract

The antiapoptotic transcription factor NF-kappaB is constitutively activated in many cancers and is important for cytokine-mediated progression and metastatic movement of tumors. Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene whose mechanisms of action are poorly understood. In this report, we demonstrate that BRMS1 decreases the transactivation potential of RelA/p65 and ameliorates the expression of NF-kappaB-regulated antiapoptotic gene products. BRMS1 immunoprecipitates with the RelA/p65 subunit of NF-kappaB with protein-protein interactions occurring at the C terminus region of the rel homology domain but not at its known transactivation domains. Moreover, BRMS1 functions as a corepressor by promoting binding of HDAC1 to RelA/p65, where it deacetylates lysine K310 on RelA/p65, which suppresses RelA/p65 transcriptional activity. Selective small interfering RNA knockdown of BRMS1 confirms that chromatin-bound BRMS1 is required for deacetylation of RelA/p65, while enhancing chromatin occupancy of HDAC1 onto the NF-kappaB-regulated promoters cIAP2 and Bfl-1/A1. We observed in cells lacking BRMS1 a dramatic increase in cell viability after the loss of attachment from the extracellular matrix. Collectively, these results suggest that BRMS1 suppresses metastasis through its ability to function as a transcriptional corepressor of antiapoptotic genes regulated by NF-kappaB.

Links

PubMed PMC1636810 Online version:10.1128/MCB.00940-06

Keywords

Acetylation; Apoptosis; Carcinoma, Non-Small-Cell Lung/metabolism; Carcinoma, Non-Small-Cell Lung/pathology; Cell Line; Cell Line, Tumor; Cell Survival; Chromatin/metabolism; Chromatin Immunoprecipitation; Escherichia coli/genetics; Glutathione Transferase/metabolism; Histone Deacetylase 1; Histone Deacetylases/metabolism; Humans; NF-kappa B/genetics; NF-kappa B/metabolism; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Plasmids/metabolism; RNA, Small Interfering; Recombinant Fusion Proteins/metabolism; Repressor Proteins/metabolism; Transcription Factor RelA/genetics; Transcription Factor RelA/metabolism; Transcription, Genetic; Transcriptional Activation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TF65

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9HCU9

F

Seeded From UniProt

complete

HUMAN:HDAC1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9HCU9

F

Seeded From UniProt

complete

HUMAN:BRMS1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BRMS1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04206

F

Seeded From UniProt

complete

HUMAN:BRMS1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13547

F

Seeded From UniProt

complete

HUMAN:BRMS1

involved_in

GO:0042981: regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRMS1

involved_in

GO:2000210: positive regulation of anoikis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRMS1

involved_in

GO:0090312: positive regulation of protein deacetylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRMS1

enables

GO:0051059: NF-kappaB binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BRMS1

involved_in

GO:0032088: negative regulation of NF-kappaB transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BRMS1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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