2. Academic Validation
  3. KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells

KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells

  • Nat Struct Mol Biol. 2019 May;26(5):361-371. doi: 10.1038/s41594-019-0219-9.
Eric Metzger 1,  Sheng Wang 1,  Sylvia Urban 1,  Dominica Willmann 1,  Andreas Schmidt 2,  Anne Offermann 3,  Anita Allen 1,  Manuela Sum 1,  Nadine Obier 1,  Félicie Cottard 1,  Svenja Ulferts 1,  Bogdan-Tiberius Preca 4,  Bianca Hermann 5,  Jochen Maurer 6,  Holger Greschik 1,  Veit Hornung 7,  Oliver Einsle 5,  Sven Perner 3,  Axel Imhof 2,  Manfred Jung 8,  Roland Schüle 9 10 11 12
Affiliations

Affiliations

  • 1 Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 2 BioMedical Center and Center of Integrated Protein Sciences (CIPSM), Ludwig-Maximilians-University of Munich, Planegg-Martinsried, Germany.
  • 3 Pathologie des Universitätsklinikums Schleswig-Holstein, Campus Lübeck und des Forschungszentrums Borstel, Leibniz Lungenzentrum, Lübeck und Borstel, Germany.
  • 4 Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
  • 5 Institut für Biochemie, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 6 Department of Obstetrics and Gynecology, University Hospital Aachen (UKA), Aachen, Germany.
  • 7 Gene Center and Department of Biochemistry, Ludwig-Maximilians-University of Munich, Munich, Germany.
  • 8 Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 9 Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Albert-Ludwigs-Universität Freiburg, Freiburg, Germany. [email protected].
  • 10 Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany. [email protected].
  • 11 BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany. [email protected].
  • 12 K-metics GmbH, Freiburg, Germany. [email protected].
PMID: 31061526 DOI: 10.1038/s41594-019-0219-9
Abstract

Histone lysine methylation is generally performed by SET domain methyltransferases and regulates chromatin structure and gene expression. Here, we identify human C21orf127 (HEMK2, N6AMT1, PrmC), a member of the seven-β-strand family of putative methyltransferases, as a novel histone lysine methyltransferase. C21orf127 functions as an obligate heterodimer with TRMT112, writing the methylation mark on lysine 12 of histone H4 (H4K12) in vitro and in vivo. We characterized H4K12 recognition by solving the crystal structure of human C21orf127-TRMT112, hereafter termed 'lysine methyltransferase 9' (KMT9), in complex with S-adenosyl-homocysteine and H4K12me1 peptide. Additional analyses revealed enrichment for KMT9 and H4K12me1 at the promoters of numerous genes encoding cell cycle regulators and control of cell cycle progression by KMT9. Importantly, KMT9 depletion severely affects the proliferation of androgen receptor-dependent, as well as that of castration- and enzalutamide-resistant prostate Cancer cells and xenograft tumors. Our data link H4K12 methylation with KMT9-dependent regulation of androgen-independent prostate tumor cell proliferation, thereby providing a promising paradigm for the treatment of castration-resistant prostate Cancer.

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