title: Demonstration that drug-targeted down-regulation of MYC in non-Hodgkins lymphoma is directly mediated through the promoter G-quadruplex.
abstract: Most transcription of the MYC proto-oncogene initiates in the near upstream promoter, within which lies the nuclease hypersensitive element (NHE) III(1) region containing the CT-element. This dynamic stretch of DNA can form at least three different topologies: single-stranded DNA, double-stranded DNA, or higher order secondary structures that silence transcription. In the current report, we identify the ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer of the MYC G-quadruplex (G4). In cells, GQC-05 induced cytotoxicity with corresponding decreased MYC mRNA and altered protein binding to the NHE III(1) region, in agreement with a G4 stabilizing compound. We further describe a unique feature of the Burkitt's lymphoma cell line CA46 that allowed us to clearly demonstrate the mechanism and location of action of GQC-05 within this region of DNA and through the G4. Most importantly, these data present, as far as we are aware, the most direct evidence of intracellular G4-mediated control of a particular promoter.
authors.affiliation: College of Pharmacy, University of Arizona, Tucson, Arizona 85721, USA.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Brown
authors.forename: Forest L
authors.initials: FL
authors.lastname: Danford
authors.forename: Vijay
authors.initials: V
authors.lastname: Gokhale
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Hurley
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Brooks
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005091:Exons / Q000235:genetics; D054856:G-Quadruplexes / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: C529584:9-(dimethylaminoethoxy)ellipticine; D000970:Antineoplastic Agents; D004611:Ellipticines; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger