Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.
Nature communications. 2025 Jan 30*** epublish ***
Yanhan Jia, Sheng Wang, Sylvia Urban, Judith M Müller, Manuela Sum, Qing Wang, Helena Bauer, Uwe Schulte, Heike Rampelt, Nikolaus Pfanner, Katrin M Schüle, Axel Imhof, Ignasi Forné, Christopher Berlin, August Sigle, Christian Gratzke, Holger Greschik, Eric Metzger, Roland Schüle
Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany., Complete Omics Inc., Baltimore, MD, USA., Institute of Physiology II, Faculty of Medicine, University of Freiburg, Freiburg, Germany., CIBSS Centre of Biological Signalling Studies, University of Freiburg, Freiburg, Germany., Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Institute Biomedical Center, Protein Analysis Unit, Faculty of Medicine, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany., Department of General and Visceral Surgery, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany. ., Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität Freiburg, Freiburg, Germany. .