title: Cell-based high-throughput compound screening reveals functional interaction between oncofetal HMGA2 and topoisomerase I.
abstract: HMGA2 is an important chromatin factor that interacts with DNA via three AT-hook domains, thereby regulating chromatin architecture and transcription during embryonic and fetal development. The protein is absent from differentiated somatic cells, but aberrantly re-expressed in most aggressive human neoplasias where it is causally linked to cell transformation and metastasis. DNA-binding also enables HMGA2 to protect cancer cells from DNA-damaging agents. HMGA2 therefore is considered to be a prime drug target for many aggressive malignancies. Here, we have developed a broadly applicable cell-based reporter system which can identify HMGA2 antagonists targeting functionally important protein domains, as validated with the known AT-hook competitor netropsin. In addition, high-throughput screening can uncover functional links between HMGA2 and cellular factors important for cell transformation. This is demonstrated with the discovery that HMGA2 potentiates the clinically important topoisomerase I inhibitor irinotecan/SN-38 in trapping the enzyme in covalent DNA-complexes, thereby attenuating transcription.
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors: Sabrina
authors: S
authors: Peter
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors: Haojie
authors: H
authors: Yu
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors: Roland
authors: R
authors: Ivanyi-Nagy
authors: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore pdroge@ntu.edu.sg.
authors: Peter
authors: P
authors: Dröge
mesh_terms: D000595:Amino Acid Sequence; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000502:physiology*; D004795:Enzyme Stability; D017930:Genes, Reporter; D057809:HEK293 Cells; D025743:HMGA2 Protein / Q000502:physiology*; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D000077146:Irinotecan; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D009429:Netropsin / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
chemical_list: D025743:HMGA2 Protein; D059004:Topoisomerase I Inhibitors; D009429:Netropsin; D000077146:Irinotecan; D049410:Luciferases, Renilla; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin