TY  - JOUR
AU  - Jia, Yanhan
AU  - Wang, Sheng
AU  - Urban, Sylvia
AU  - Müller, Judith M
AU  - Sum, Manuela
AU  - Wang, Qing
AU  - Bauer, Helena
AU  - Schulte, Uwe
AU  - Rampelt, Heike
AU  - Pfanner, Nikolaus
AU  - Schüle, Katrin M
AU  - Imhof, Axel
AU  - Forné, Ignasi
AU  - Berlin, Christopher
AU  - Sigle, August
AU  - Gratzke, Christian
AU  - Greschik, Holger
AU  - Metzger, Eric
AU  - Schüle, Roland
TI  - Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00259
SP  - 1191
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Prostatic Neoplasms: pathology
KW  - Prostatic Neoplasms: genetics
KW  - Prostatic Neoplasms: metabolism
KW  - Prostatic Neoplasms: enzymology
KW  - Male
KW  - Animals
KW  - Mitochondria: metabolism
KW  - Histone-Lysine N-Methyltransferase: metabolism
KW  - Histone-Lysine N-Methyltransferase: genetics
KW  - Mice
KW  - Cell Line, Tumor
KW  - Cell Proliferation
KW  - Pyruvate Dehydrogenase Complex: metabolism
KW  - Pyruvate Dehydrogenase Complex: genetics
KW  - Dihydrolipoyllysine-Residue Acetyltransferase: metabolism
KW  - Dihydrolipoyllysine-Residue Acetyltransferase: genetics
KW  - Methylation
KW  - Lipogenesis: genetics
KW  - Histone-Lysine N-Methyltransferase (NLM Chemicals)
KW  - Pyruvate Dehydrogenase Complex (NLM Chemicals)
KW  - Dihydrolipoyllysine-Residue Acetyltransferase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39885202
DO  - DOI:10.1038/s41467-025-56492-8
UR  - https://inrepo02.dkfz.de/record/298361
ER  -