title: OTX2 represses myogenic and neuronal differentiation in medulloblastoma cells.
abstract: The brain development transcription factor OTX2 is overexpressed and/or genomically amplified in most medulloblastomas, but the mechanistic basis for its contributions in this setting are not understood. In this study, we identified OTX2 as a transcriptional repressor and a gatekeeper of myogenic and neuronal differentiation in medulloblastoma cells. OTX2 binds to the MyoD1 core enhancer through its homeobox domain, and the remarkable repressor activity exhibited by the homeobox domain renders OTX2 transcriptionally repressive. RNA interference-mediated attenuation of OTX2 expression triggered myogenic and neuronal differentiation in vitro and prolonged the survival in an orthotopic medulloblastoma mouse model. Conversely, inducing myogenic conversion of medulloblastoma cells led to the loss of OTX2 expression. In medullomyoblastoma, a medulloblastoma subtype containing muscle elements, myogenic cells share cytogenetic signatures with the primitive tumor cells and OTX2 expression was lost in the differentiated myogenic cells. Thus, OTX2 functions via its homeobox domain as a suppressor of differentiation, and the loss of OTX2 expression is linked to the myogenesis in medullomyoblastoma. Together, our findings illustrate the origin of muscle cells in medullomyoblastomas and the oncogenic mechanism of OTX2 as a repressor of diverse differentiating potential.
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. rbai1@jhmi.edu
authors.forename: Ren-Yuan
authors.initials: RY
authors.lastname: Bai
authors.forename: Verena
authors.initials: V
authors.lastname: Staedtke
authors.forename: Hart G
authors.initials: HG
authors.lastname: Lidov
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology; D002522:Chlorocebus aethiops; D005260:Female; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology*; D017570:MyoD Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D051857:Otx Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D017570:MyoD Protein; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D034741:RNA, Small Interfering; D012097:Repressor Proteins