STANDARD_NAME KESHELAVA_MULTIPLE_DRUG_RESISTANCE SYSTEMATIC_NAME M12618 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KESHELAVA_MULTIPLE_DRUG_RESISTANCE NAMESPACE AFFY_HG_U133 DESCRIPTION_BRIEF Genes up-regulated in multiple drug resistant neuroblastoma cell lines. DESCRIPTION_FULL BACKGROUND: Genes that are overexpressed in multidrug-resistant neuroblastomas relative to drug-sensitive neuroblastomas may provide targets for modulating drug resistance. METHODS: We used microarrays to compare the gene expression profile of two drug-sensitive neuroblastoma cell lines with that of three multidrug-resistant neuroblastoma cell lines. RNA expression of selected overexpressed genes was quantified in 17 neuroblastoma cell lines by reverse transcription-polymerase chain reaction (RT-PCR). Small-interfering RNAs (siRNAs) were used for silencing gene expression. Cytotoxicity of melphalan, carboplatin, etoposide, and vincristine and cytotoxic synergy (expressed as combination index calculated by CalcuSyn software, where combination index < 1 indicates synergy and > 1 indicates antagonism) were measured in cell lines with a fluorescence-based assay of cell viability. All statistical tests were two-sided. RESULTS: A total of 94 genes were overexpressed in the multidrug-resistant cell lines relative to the drug-sensitive cell lines. Nine genes were selected for RT-PCR analysis, of which four displayed higher mRNA expression in the multidrug-resistant lines than in the drug-sensitive lines: histone deacetylase 1 (HDAC1; 2.3-fold difference, 95% confidence interval [CI] = 1.0-fold to 3.5-fold, P = .025), nuclear transport factor 2-like export factor (4.2-fold difference, 95% CI = 1.7-fold to 7.6-fold, P = .0018), heat shock 27-kDa protein 1 (2.5-fold difference, 95% CI = 1.0-fold to 87.7-fold, P = .028), and TAF12 RNA polymerase II, TATA box-binding protein-associated factor, 20 kDa (2.2-fold, 95% CI = 0.9-fold to 6.0-fold, P = .051). siRNA knockdown of HDAC1 gene expression sensitized CHLA-136 neuroblastoma cells to etoposide up to fivefold relative to the parental cell line or scrambled siRNA-transfected cells (P<.001). Cytotoxicity of the histone deacetylase inhibitor depsipeptide was tested in combination with melphalan, carboplatin, etoposide, or vincristine in five multidrug-resistant neuroblastoma cell lines, and synergistic cytotoxicity was demonstrated at a 90% cell kill of treated cells (combination index < 0.8) in all cell lines. CONCLUSION: High HDAC1 mRNA expression was associated with multidrug resistance in neuroblastoma cell lines, and inhibition of HDAC1 expression or activity enhanced the cytotoxicity of chemotherapeutic drugs in multidrug-resistant neuroblastoma cell lines. Thus, HDAC1 is a potential therapeutic target in multidrug-resistant neuroblastoma. PMID 17623797 GEOID AUTHORS Keshelava N,Davicioni E,Wan Z,Ji L,Sposto R,Triche TJ,Reynolds CP CONTRIBUTOR Jessica Robertson CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Table 1S FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS 200075_s_at,200791_s_at,200837_at,200929_at,201209_at,201340_s_at,201341_at,201841_s_at,202201_at,202366_at,202518_at,202869_at,202879_s_at,202928_s_at,203227_s_at,203242_s_at,203495_at,203522_at,203775_at,203824_at,204306_s_at,204949_at,205186_at,205561_at,206106_at,206352_s_at,207287_at,207370_at,207662_at,208816_x_at,208932_at,208978_at,209310_s_at,209463_s_at,209629_s_at,209698_at,209917_s_at,210075_at,210241_s_at,210355_at,210415_s_at,210474_s_at,211329_x_at,211719_x_at,211792_s_at,212464_s_at,212645_x_at,213448_at,213696_s_at,213733_at,213804_at,214190_x_at,214278_s_at,214296_x_at,214744_s_at,214867_at,215238_s_at,215269_at,215721_at,215760_s_at,215814_at,217007_s_at,217134_at,217577_at,217751_at,217797_at,217977_at,218017_s_at,218175_at,218279_s_at,218291_at,218321_x_at,218415_at,218417_s_at,218436_at,218598_at,218636_s_at,218676_s_at,218802_at,218894_s_at,219047_s_at,219063_at,219208_at,219309_at,219348_at,219556_at,219687_at,220097_s_at,220646_s_at,221334_s_at,222054_at,222314_x_at,38157_at,65438_at GENE_SYMBOLS GUK1,IQGAP1,BCAP31,TMED10,HDAC1,ENC1,ENC1,HSPB1,BLVRB,ACADS,BCL7B,OAS1,CYTH1,PHF1,TSPAN31,PDLIM5,LRRC14,CCS,SLC25A13,TSPAN8,CD151,ICAM3,DNALI1,KCTD17,MAPK12,PEX10,,IBSP,TBX1,ANXA2P2,PPP4C,CRIP2,CASP4,TAF12,NXT2,CCHCR1,TP53TG1,MARCHF2,TP53TG1,PTHLH,ODF2,CDK11B,HFE,FN1,CDKN2C,FN1,BABAM2,,MED8,MYO1F,INPP5B,GGA2,,IZUMO4,RPL23,ZSWIM8-AS1,DOCK9,,IGHV5-51,SBNO2,,ADAM15,,,GSTK1,UFC1,MSRB1,HGSNAT,CCDC92,,LAMTOR2,STYXL1,VPS33B,SLC48A1,SIL1,RINT1,MAN1B1,PCTP,MCUB,MAGOHB,ZNF668,C1orf35,FBXO11,C22orf46P,USE1,TEDC2,HHAT,TMEM104,KLRF1,FOXP3,PPIEL,,DXO,MEAK7 FOUNDER_NAMES