title: Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation.
abstract: Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signaling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2-CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution.
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Metzger
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Dominica
authors.initials: D
authors.lastname: Willmann
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.|Diamond Light Source, Didcot, UK.
authors.forename: Joel
authors.initials: J
authors.lastname: McMillan
authors.affiliation: Adolf-Butenandt Institut, University of Munich, München, Germany.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Forne
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Metzger
authors.affiliation: Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gerhardt
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.|Center for Biological Systems Analysis, Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Petroll
authors.affiliation: Pathology Network of the University Hospital of Luebeck and Leibniz Research Center Borstel, Luebeck and Borstel, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: von Maessenhausen
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Urban
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Schott
authors.affiliation: Department of Carcinogenesis, University of Texas, Smithville, Texas, USA.
authors.forename: Alexsandra
authors.initials: A
authors.lastname: Espejo
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Adrien
authors.initials: A
authors.lastname: Eberlin
authors.affiliation: Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wohlwend
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.
authors.forename: Katrin M
authors.initials: KM
authors.lastname: Schüle
authors.affiliation: Department of New Therapeutic Concept Discovery, Boehringer Ingelheim, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schleicher
authors.affiliation: Pathology Network of the University Hospital of Luebeck and Leibniz Research Center Borstel, Luebeck and Borstel, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Department of Carcinogenesis, University of Texas, Smithville, Texas, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.|Deutsches Konsortium für Translationale Krebsforschung, Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.affiliation: Center for Biological Systems Analysis, Freiburg, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Diamond Light Source, Didcot, UK.
authors.forename: Ralf
authors.initials: R
authors.lastname: Flaig
authors.affiliation: Adolf-Butenandt Institut, University of Munich, München, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Imhof
authors.affiliation: Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.|Centre of Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Einsle
authors.affiliation: Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany.|Deutsches Konsortium für Translationale Krebsforschung, Freiburg, Germany.|Centre of Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Schüle
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D004265:DNA Helicases / Q000032:analysis / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000378:metabolism; D056466:Histone Demethylases / Q000032:analysis / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation; D008958:Models, Molecular; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000032:analysis / Q000378:metabolism*; D014158:Transcription, Genetic; D014178:Translocation, Genetic
chemical_list: C410798:AR protein, human; D004268:DNA-Binding Proteins; D006649:Histocompatibility Antigens; D015514:Oncogene Proteins, Fusion; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; D056466:Histone Demethylases; C495195:KDM1A protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D004265:DNA Helicases; C080359:CHD1 protein, human