Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth
Abstract 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 mitochondri...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56492-8 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yanhan Jia |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-98fbab92ad454a78befd48923b77c4ce |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-98fbab92ad454a78befd48923b77c4ce2025-02-02T12:31:55ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-56492-8Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growthYanhan Jia0Sheng Wang1Sylvia Urban2Judith M. Müller3Manuela Sum4Qing Wang5Helena Bauer6Uwe Schulte7Heike Rampelt8Nikolaus Pfanner9Katrin M. Schüle10Axel Imhof11Ignasi Forné12Christopher Berlin13August Sigle14Christian Gratzke15Holger Greschik16Eric Metzger17Roland Schüle18Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgComplete Omics Inc.Klinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgInstitute of Physiology II, Faculty of Medicine, University of FreiburgCIBSS Centre of Biological Signalling Studies, University of FreiburgCIBSS Centre of Biological Signalling Studies, University of FreiburgInstitute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of FreiburgInstitute Biomedical Center, Protein Analysis Unit, Faculty of Medicine, Ludwig-Maximilians-Universität MünchenInstitute Biomedical Center, Protein Analysis Unit, Faculty of Medicine, Ludwig-Maximilians-Universität MünchenDepartment of General and Visceral Surgery, Faculty of Medicine, University of FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgKlinik für Urologie und Zentrale Klinische Forschung, Klinikum der Universität FreiburgAbstract 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.https://doi.org/10.1038/s41467-025-56492-8 |
| spellingShingle | 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 Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth Nature Communications |
| title | Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth |
| title_full | Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth |
| title_fullStr | Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth |
| title_full_unstemmed | Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth |
| title_short | Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth |
| title_sort | mitochondrial kmt9 methylates dlat to control pyruvate dehydrogenase activity and prostate cancer growth |
| url | https://doi.org/10.1038/s41467-025-56492-8 |
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