title: Mechanism and Role of SOX2 Repression in Seminoma: Relevance to Human Germline Specification.
abstract: Human male germ cell tumors (GCTs) are derived from primordial germ cells (PGCs). The master pluripotency regulator and neuroectodermal lineage effector transcription factor SOX2 is repressed in PGCs and the seminoma (SEM) subset of GCTs. The mechanism of SOX2 repression and its significance to GC and GCT development currently are not understood. Here, we show that SOX2 repression in SEM-derived TCam-2 cells is mediated by the Polycomb repressive complex (PcG) and the repressive H3K27me3 chromatin mark that are enriched at its promoter. Furthermore, SOX2 repression in TCam-2 cells can be abrogated by recruitment of the constitutively expressed H3K27 demethylase UTX to the SOX2 promoter through retinoid signaling, leading to expression of neuronal and other lineage genes. SOX17 has been shown to initiate human PGC specification, with its target PRDM1 suppressing mesendodermal genes. Our results are consistent with a role for SOX2 repression in normal germline development by suppressing neuroectodermal genes.
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Kushwaha
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nirmala
authors.initials: N
authors.lastname: Jagadish
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Manjunath
authors.initials: M
authors.lastname: Kustagi
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Geetu
authors.initials: G
authors.lastname: Mendiratta
authors.affiliation: Department of Surgery, Weill Cornell Medical Center, New York, NY 10065, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Seandel
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Soni
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Korkola
authors.affiliation: Cancer Genetics, Inc., Rutherford, NJ 07070, USA.
authors.forename: Venkata
authors.initials: V
authors.lastname: Thodima
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: George J
authors.initials: GJ
authors.lastname: Bosl
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: chagantr@mskcc.org.
authors.forename: R S K
authors.initials: RSK
authors.lastname: Chaganti
mesh_terms: D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005854:Germ Cells / Q000473:pathology; D056466:Histone Demethylases / Q000235:genetics; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D063146:Polycomb-Group Proteins / Q000235:genetics; D000074462:Positive Regulatory Domain I-Binding Factor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D055760:SOXF Transcription Factors / Q000235:genetics*; D018239:Seminoma / Q000235:genetics* / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D002843:Chromatin; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; C109188:SOX17 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D055760:SOXF Transcription Factors; C087042:PRDM1 protein, human; D056466:Histone Demethylases; C523998:KDM6A protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1