Hormone Dependent Cancer

We have identified lysine methyltransferase 9 (KMT9) as a novel target for the treatment of prostate cancer. KMT9 is an obligatory heterodimer composed of KMT9a and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1). 

In prostate and other tumours, KMT9 controls transcription of target genes involved in cell cycle regulation thereby promoting tumour cell proliferation. Depletion or enzymatic inactivation of KMT9 blocks proliferation of castration- and enzalutamide-resistant prostate cancer cells independently of AR signalling in vitro and in xenograft mouse models. In PCa cells, mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase at lysine 596 and thereby controls de novo lipogenesis and proliferation. The observation that the enzymatic activity of KMT9 is required to control tumour cell growth presents KMT9 as an attractive therapeutic target. 

Therefore, we developed first-in-class, potent and selective KMT9 small-molecule inhibitors (KMT9i) that display cellular target engagement with no general cellular toxicity. KMT9 inhibition results in reduced H4K12me1 cellular levels, down-regulation of KMT9 target genes involved in cell cycle regulation, and suppression of tumour cell growth. Recently, we identified KMT9 as a major regulator of immunosuppression in prostate cancer and our findings suggest that targeting KMT9 sensitizes prostate cancer to immune checkpoint therapy

Literature

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, Jung M and Schüle R. KMT9 monomethylates histone H4 lysine 12 and controls proliferation of prostate cancer cells. Nature Structural & Molecular Biology, 2019. 26: 361-371. doi 10.1038/s41594-019-0219-9.

Baumert HM, Metzger E, Fahrner M, George J, Thomas RK, Schilling O, Schüle R. Depletion of histone methyltransferase KMT9 inhibits lung cancer cell proliferation by inducing non-apoptotic cell death. Cancer Cell Int, 2020. 20: 52. doi 10.1186/s12935-020-1141-2.

Berlin C, Cottard F, Willmann D, Urban S, Tirier SM, Marx L, Rippe K, Schmitt M, Petrocelli V, Greten FR, Fichtner-Feigl S, Kesselring R, Metzger E, Schüle R. KMT9 Controls Stemness and Growth of Colorectal Cancer. Cancer Res, 2022. 82: 210-220. doi 10.1158/0008-5472.Can-21-1261.

Totonji S, Ramos-Triguero A, Willmann D, Sum M, Urban S, Bauer H, Rieder A, Wang S, Greschik H, Metzger E*, R. Schüle*. Lysine Methyltransferase 9 (KMT9) Is an Actionable Target in Muscle-Invasive Bladder Cancer. Cancers (Basel), 2024. 16. doi 10.3390/cancers16081532. *co-senior authors

Jia Y, Wang S, Urban S, Muller JM, Sum M, Wang Q, Bauer H, Schulte U, Rampelt H, Pfanner N, Schüle KM, Imhof A, Forne I, Berlin C, Sigle A, Gratzke C, Greschik H, Metzger E*, R. Schüle*. Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth. Nat Commun, 2025. 16: p. 1191. doi: 10.1038/s41467-025-56492-8. * co-senior author.

Wang S, Klein SO, Urban S, Staudt M, Barthes NPF, Willmann D, Bacher J, Sum M, Bauer H, Peng L, Rennar GA, Gratzke C, Schüle KM, Zhang L, Einsle O, Greschik H, MacLeod C, Thomson CG, Jung M, Metzger E*, Schüle R*. Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity. Nat Commun, 2024. 15: p. 43. doi: 10.1038/s41594-019-0219-9. *co-senior author