title: Histone deacetylase inhibitor trichostatin A represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines.
abstract: OBJECTIVE
  Estrogen receptor alpha (ERalpha)-positive breast cancer cell lines are up to 10 times more sensitive than ERalpha-negative cell lines to the antiproliferative activity of the histone deacetylase inhibitor trichostatin A (TSA). The purpose of the study was to investigate the mechanisms underlying this differential response.
  
  
  RESULTS
  In the ERalpha-positive MCF-7 cell line, TSA repressed ERalpha and cyclin D1 transcription and induced ubiquitin dependent proteasomal degradation of cyclin D1, leading primarily to G(1)-S-phase cell cycle arrest. By contrast, cyclin D1 degradation was enhanced but its transcription unaffected by TSA in the ERalpha-negative MDA-MB-231 cell line, which arrested in G(2)-M phase. Cyclin D1 degradation involved Skp2/p45, a regulatory component of the Skp1/Cullin/F-box complex; silencing SKP2 gene expression by RNA interference stabilized cyclin D1 and abrogated the cyclin D1 down-regulation response to TSA.
  
  
  CONCLUSIONS
  Tamoxifen has been shown to inhibit ERalpha-mediated cyclin D1 transcription, and acquired resistance to tamoxifen is associated with a shift to ERalpha-independent cyclin D1 up-regulation. Taken together, our data show that TSA effectively induces cyclin D1 down-regulation through both ERalpha-dependent and ERalpha-independent mechanisms, providing an important new strategy for combating resistance to antiestrogens.
authors.affiliation: Department of Cancer Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom.
authors.forename: John Patrick
authors.initials: JP
authors.lastname: Alao
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.forename: Laki
authors.initials: L
authors.lastname: Buluwela
authors.forename: Walter
authors.initials: W
authors.lastname: Bordogna
authors.forename: Peter
authors.initials: P
authors.lastname: Lockey
authors.forename: Rana
authors.initials: R
authors.lastname: Varshochi
authors.forename: Alexandra V
authors.initials: AV
authors.lastname: Stavropoulou
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: David M
authors.initials: DM
authors.lastname: Vigushin
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D010450:Endopeptidases / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D034622:RNA Interference; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015853:Cysteine Proteinase Inhibitors; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007976:Leupeptins; D044786:S-Phase Kinase-Associated Proteins; D013629:Tamoxifen; D019938:Cyclin D1; C012589:trichostatin A; D010450:Endopeptidases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde