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

Eric Metzger; Sheng Wang; Sylvia Urban; Dominica Willmann; Andreas Schmidt; Anne Offermann; Anita Allen; Manuela Sum; Nadine Obier; Félicie Cottard; Svenja Ulferts; Bogdan Tiberius Preca; Bianca Hermann; Jochen Maurer; Holger Greschik; Veit Hornung; Oliver Einsle; Sven Perner; Axel Imhof; Manfred Jung; Roland Schüle

doi:10.1038/s41594-019-0219-9

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

Eric Metzger, Sheng Wang, Sylvia Urban, Dominica Willmann, Andreas Schmidt, Anne Offermann, Anita Allen, Manuela Sum, Nadine Obier, Félicie Cottard, Svenja Ulferts, Bogdan Tiberius Preca, Bianca Hermann, Jochen Maurer, Holger Greschik, Veit Hornung, Oliver Einsle, Sven Perner, Axel Imhof, Manfred JungRoland Schüle^*

^*Corresponding author for this work

Institute of Pathology

74 Citations (Scopus)

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.

Original language	English
Journal	Nature Structural and Molecular Biology
Volume	26
Issue number	5
Pages (from-to)	361-371
Number of pages	11
ISSN	1545-9993
DOIs	https://doi.org/10.1038/s41594-019-0219-9
Publication status	Published - 01.05.2019

Funding

We thank Z. Culig (Department of Urology, Medical University of Innsbruck, Innsbruck, Austria) and R. Schneider (Institute of Functional Epigenetics, Helmholtz Zentrum München, Ludwig Maximilians Universität, Munich) for providing reagents. We are obliged to A. Rieder for providing excellent technical assistance. We are grateful to Swiss Light Source (SLS) beam line scientists for the technical support. This work was supported by grants of the European Research Council (ERC AdGrant 322844) and the 15-1 to R. SFB 992, 850, 746, and Schu688/15-1 to R.S.

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Metzger, E., Wang, S., Urban, S., Willmann, D., Schmidt, A., Offermann, A., Allen, A., Sum, M., Obier, N., Cottard, F., Ulferts, S., Preca, B. T., Hermann, B., Maurer, J., Greschik, H., Hornung, V., Einsle, O., Perner, S., Imhof, A., ... Schüle, R. (2019). KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nature Structural and Molecular Biology, 26(5), 361-371. https://doi.org/10.1038/s41594-019-0219-9

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title = "KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells",

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 {\textquoteleft}lysine methyltransferase 9{\textquoteright} (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.",

author = "Eric Metzger and Sheng Wang and Sylvia Urban and Dominica Willmann and Andreas Schmidt and Anne Offermann and Anita Allen and Manuela Sum and Nadine Obier and F{\'e}licie Cottard and Svenja Ulferts and Preca, \{Bogdan Tiberius\} and Bianca Hermann and Jochen Maurer and Holger Greschik and Veit Hornung and Oliver Einsle and Sven Perner and Axel Imhof and Manfred Jung and Roland Sch{\"u}le",

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Metzger, E, Wang, S, Urban, S, Willmann, D, Schmidt, A, Offermann, A, Allen, A, Sum, M, Obier, N, Cottard, F, Ulferts, S, Preca, BT, Hermann, B, Maurer, J, Greschik, H, Hornung, V, Einsle, O, Perner, S, Imhof, A, Jung, M & Schüle, R 2019, 'KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells', Nature Structural and Molecular Biology, vol. 26, no. 5, pp. 361-371. https://doi.org/10.1038/s41594-019-0219-9

TY - JOUR

T1 - KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells

AU - Metzger, Eric

AU - Wang, Sheng

AU - Urban, Sylvia

AU - Willmann, Dominica

AU - Schmidt, Andreas

AU - Offermann, Anne

AU - Allen, Anita

AU - Sum, Manuela

AU - Obier, Nadine

AU - Cottard, Félicie

AU - Ulferts, Svenja

AU - Preca, Bogdan Tiberius

AU - Hermann, Bianca

AU - Maurer, Jochen

AU - Greschik, Holger

AU - Hornung, Veit

AU - Einsle, Oliver

AU - Perner, Sven

AU - Imhof, Axel

AU - Jung, Manfred

AU - Schüle, Roland

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85065328747

U2 - 10.1038/s41594-019-0219-9

DO - 10.1038/s41594-019-0219-9

M3 - Journal articles

C2 - 31061526

AN - SCOPUS:85065328747

SN - 1545-9993

VL - 26

SP - 361

EP - 371

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 5

ER -

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

Abstract

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