PXD053942

PXD053942 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity, de novo lipogenesis, and prostate cancer growth
Description	Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identified lysine methyltransferase (KMT)9 as a novel 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, which can be rescued with exogenous KMT9 targeted to mitochondria. Similarly, comparable defects caused by DLAT depletion can be rescued with exogenous DLAT, but not with a methylation-defective DLAT mutant. Concomitant chemical inhibition of de novo lipogenesis and KMT9 depletion more efficiently impair PCa cell proliferation than either treatment alone. Importantly, KMT9 controls PDC activity, de novo lipogenesis, and tumor growth in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a novel mechanism of PDC regulation and the first example of a histone methyltransferase with nuclear and mitochondrial functions. The exceptional dependency on mitochondrial KMT9 allows to develop novel therapeutic strategies to fight PCa.
HostingRepository	PRIDE
AnnounceDate	2024-12-03
AnnouncementXML	Submission_2024-12-03_07:13:08.408.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Axel Imhof
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-15 00:57:26	ID requested
⏵ 1	2024-12-03 07:13:08	announced

Dataset with its publication pending

submitter keyword: Protein Methylation, Metabolism, Mitochondria

Axel Imhof
contact affiliation	Prof. Dr. Axel Imhof Histone Modifications Group Zentrallabor für Proteinanalytik BioMedical Center Faculty of Medicine Ludwig-Maximilians-University of Munich Großhadernerstr. 9 82152 Planegg-Martinsried GERMANY
contact email	imhof@lmu.de
lab head
Axel Imhof
contact affiliation	BioMedical Center
contact email	imhof@lmu.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053942
     1. Label: PRIDE project
     2. Name: Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity, de novo lipogenesis, and prostate cancer growth