title: Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma.
abstract: Lysine-specific demethylase 1 (GeneID 23028), a flavin-dependent monoamine oxidoreductase and a histone demethylase, serves as an epigenetic coregulator of transcription. Lysine-specific demethylase 1 is up-regulated in neuroblastoma and in bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers, and its overexpression drives the cell cycle of otherwise nontransformed human cells, suggesting oncogenic properties. Lysine-specific demethylase 1 was recently reported to be also overexpressed in several different mesenchymal tumors. We investigated lysine-specific demethylase 1 expression in over 500 sarcomas by gene expression profiling and tissue microarray-coupled immunohistochemical analyses and confirmed lysine-specific demethylase 1 overexpression in rhabdomyosarcoma and synovial sarcoma. We also show for the first time that lysine-specific demethylase 1 is also overexpressed in chondrosarcoma, Ewing's sarcoma, and osteosarcoma wherein it localizes in cell nuclei. We further show that a US Food and Drug Administration-approved drug that inhibits lysine-specific demethylase 1 also inhibits chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma cell growth in vitro. These data suggest that lysine-specific demethylase 1 plays a role in sarcoma pathology and that lysine-specific demethylase 1 inhibition strategies might represent a novel means to inhibiting growth of lysine-specific demethylase 1-overexpressing sarcomas.
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, A-1090 Vienna, Austria. idriss.bennani@ccri.at
authors.forename: Idriss M
authors.initials: IM
authors.lastname: Bennani-Baiti
authors.forename: Isidro
authors.initials: I
authors.lastname: Machado
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart-Bosch
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kovar
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002813:Chondrosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014191:Tranylcypromine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014191:Tranylcypromine; D056466:Histone Demethylases; C495195:KDM1A protein, human