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10.18632/oncotarget.13376

http://scihub22266oqcxt.onion/10.18632/oncotarget.13376
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C5348313!5348313 !27863397
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suck abstract from ncbi


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pmid27863397
      Oncotarget 2016 ; 7 (49 ): 80190-80207
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  • Targeting GLI by GANT61 involves mechanisms dependent on inhibition of both transcription and DNA licensing #MMPMID27863397
  • Zhang R ; Wu J ; Ferrandon S ; Glowacki KJ ; Houghton JA
  • Oncotarget 2016[Dec]; 7 (49 ): 80190-80207 PMID27863397 show ga
  • The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter. Pretreatment of HT29 cells with ?-amanitin reduced GANT61-induced ?H2AX foci. Co-localization of GLI1 and BrdU foci, inhibited by GANT61, indicated GLI1 and DNA replication to be linked. By co-immunoprecipitation and confocal microscopy, GLI1 co-localized with the DNA licensing factors ORC4, CDT1, and MCM2. Significant co-localization of GLI1 and ORC4 was inhibited by GANT61, and enrichment of ORC4 occurred at the GLI binding site in the FOXM1 promoter. CDT1 was found to be a transcription target of GLI1. Overexpression of CDT1 in HT29 and SW480 cells reduced GANT61-induced cell death, gH2AX foci, and cleavage of caspase-3. Data demonstrate involvement of transcription and of DNA replication licensing factors by non-transcriptional and transcriptional mechanisms in the GLI-dependent mechanism of action of GANT61.
  • |Antineoplastic Agents/*pharmacology [MESH]
  • |Binding Sites [MESH]
  • |Cell Cycle Proteins/genetics/metabolism [MESH]
  • |Cell Death/drug effects [MESH]
  • |Colonic Neoplasms/*drug therapy/genetics/metabolism/pathology [MESH]
  • |DNA Replication/*drug effects [MESH]
  • |Dose-Response Relationship, Drug [MESH]
  • |Forkhead Box Protein M1/genetics/metabolism [MESH]
  • |Gene Expression Regulation, Neoplastic/*drug effects [MESH]
  • |HT29 Cells [MESH]
  • |Histones/metabolism [MESH]
  • |Humans [MESH]
  • |Minichromosome Maintenance Complex Component 2/genetics/metabolism [MESH]
  • |Nuclear Proteins/genetics/metabolism [MESH]
  • |Origin Recognition Complex/genetics/metabolism [MESH]
  • |Promoter Regions, Genetic [MESH]
  • |Pyridines/*pharmacology [MESH]
  • |Pyrimidines/*pharmacology [MESH]
  • |RNA Polymerase II/genetics/metabolism [MESH]
  • |Transcription Factors/genetics/metabolism [MESH]
  • |Transcription, Genetic/*drug effects [MESH]
  • |Transcriptional Elongation Factors/genetics/metabolism [MESH]
  • |Transfection [MESH]


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