title: The histone demethylase KDM3A is a microRNA-22-regulated tumor promoter in Ewing Sarcoma.
abstract: Ewing Sarcoma is a biologically aggressive bone and soft tissue malignancy affecting children and young adults. Ewing Sarcoma pathogenesis is driven by EWS/Ets fusion oncoproteins, of which EWS/Fli1 is the most common. We have previously shown that microRNAs (miRs) regulated by EWS/Fli1 contribute to the pro-oncogenic program in Ewing Sarcoma. Here we show that miR-22, an EWS/Fli1-repressed miR, is inhibitory to Ewing Sarcoma clonogenic and anchorage-independent cell growth, even at modest overexpression levels. Our studies further identify the H3K9me1/2 histone demethylase KDM3A (JMJD1A/JHDM2A) as a new miR-22-regulated gene. We show that KDM3A is overexpressed in Ewing Sarcoma, and that its depletion inhibits clonogenic and anchorage-independent growth in multiple patient-derived cell lines, and tumorigenesis in a xenograft model. KDM3A depletion further results in augmentation of the levels of the repressive H3K9me2 histone mark, and downregulation of pro-oncogenic factors in Ewing Sarcoma. Together, our studies identify the histone demethylase KDM3A as a new, miR-regulated, tumor promoter in Ewing Sarcoma.
authors.affiliation: Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Parrish
authors.affiliation: Cancer Biology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sechler
authors.affiliation: Department of Medicine, University of Illinois, Chicago, IL, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Winn
authors.affiliation: 1] Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA [2] Cancer Biology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jedlicka
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation; D057890:Epigenomics; D064593:Heterografts; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
chemical_list: C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human