title: Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer.
abstract: ARHI is a maternally imprinted tumor suppressor gene that is expressed in normal breast and ovarian epithelial cells but not in most breast and ovarian cancers. Our earlier studies showed that histone deacetylases (HDACs) in complexes with transcription factors E2F1 and E2F4 play an important role in downregulating ARHI expression in breast cancer cells. To determine which HDAC or HDACs are responsible for repressing ARHI, we cotransfected vectors expressing HDACs 1-11 with an ARHI/luciferase reporter into SKBr3 and MCF-7 breast cancer cells. Expression of multiple HDACs consistently reduced ARHI promoter activity in a dose-dependent manner. We also found that the expression level of HDACs 1-3 was higher in breast cancer cell lines than in normal breast epithelial cells. In agreement with their repressive function, depletion of HDACs 1, 3 and 11 not only significantly increased the ARHI promoter activity of the transfected reporter but also activated the transcription of the endogenous ARHI gene. Furthermore, depletion or inhibition of HDACs by small interfering RNA of HDAC11 or by trichostatin A, respectively, increased E2F acetylation. Chromatin immunoprecipitation assays revealed that HDACs 1 and 3 are bound to the ARHI promoter. Taken together, our results suggest that the activity of multiple HDACs contributes to the repression of the ARHI tumor suppressor gene in breast cancer cells. Since HDAC inhibitors are now being used to treat breast cancer, the reactivation of ARHI in these cancer cells may serve as a new biomarker with which to monitor the treatment effects.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Feng
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Luo
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.forename: Warren S-L
authors.initials: WS
authors.lastname: Liao
authors.forename: Yinhua
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000107:Acetylation; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C117386:DIRAS3 protein, human; D050687:E2F1 Transcription Factor; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; C012589:trichostatin A; D008156:Luciferases; D006655:Histone Deacetylases; D020741:rho GTP-Binding Proteins