| Literature DB >> 26751641 |
Eric Metzger1, Dominica Willmann1, Joel McMillan1,2, Ignasi Forne3, Philipp Metzger1, Stefan Gerhardt4, Kerstin Petroll1,5, Anne von Maessenhausen6, Sylvia Urban1, Anne-Kathrin Schott1, Alexsandra Espejo7, Adrien Eberlin1, Daniel Wohlwend4, Katrin M Schüle1, Michael Schleicher8, Sven Perner6, Mark T Bedford7, Manfred Jung9,10, Jörn Dengjel5, Ralf Flaig2, Axel Imhof3, Oliver Einsle4,11, Roland Schüle1,10,11.
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.Entities:
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Year: 2016 PMID： 26751641 DOI： 10.1038/nsmb.3153
Source DB: PubMed Journal: Nat Struct Mol Biol ISSN： 1545-9985 Impact factor: 15.369