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Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth

Author

Listed:
  • Yanhan Jia

    (Klinikum der Universität Freiburg
    a partnership between DKFZ and Medical Center - University of Freiburg)

  • Sheng Wang

    (Klinikum der Universität Freiburg)

  • Sylvia Urban

    (Klinikum der Universität Freiburg)

  • Judith M. Müller

    (Klinikum der Universität Freiburg)

  • Manuela Sum

    (Klinikum der Universität Freiburg)

  • Qing Wang

    (Complete Omics Inc.)

  • Helena Bauer

    (Klinikum der Universität Freiburg)

  • Uwe Schulte

    (University of Freiburg
    University of Freiburg)

  • Heike Rampelt

    (University of Freiburg
    University of Freiburg)

  • Nikolaus Pfanner

    (University of Freiburg
    University of Freiburg)

  • Katrin M. Schüle

    (University of Freiburg)

  • Axel Imhof

    (Ludwig-Maximilians-Universität München)

  • Ignasi Forné

    (Ludwig-Maximilians-Universität München)

  • Christopher Berlin

    (University of Freiburg)

  • August Sigle

    (Klinikum der Universität Freiburg)

  • Christian Gratzke

    (Klinikum der Universität Freiburg)

  • Holger Greschik

    (Klinikum der Universität Freiburg)

  • Eric Metzger

    (Klinikum der Universität Freiburg
    a partnership between DKFZ and Medical Center - University of Freiburg)

  • Roland Schüle

    (Klinikum der Universität Freiburg
    a partnership between DKFZ and Medical Center - University of Freiburg
    University of Freiburg)

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.

Suggested Citation

  • 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 & Chr, 2025. "Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56492-8
    DOI: 10.1038/s41467-025-56492-8
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    References listed on IDEAS

    as
    1. Xi Wang & Marianna Kruithof-de Julio & Kyriakos D. Economides & David Walker & Hailong Yu & M. Vivienne Halili & Ya-Ping Hu & Sandy M. Price & Cory Abate-Shen & Michael M. Shen, 2009. "A luminal epithelial stem cell that is a cell of origin for prostate cancer," Nature, Nature, vol. 461(7263), pages 495-500, September.
    2. Zhihu Ding & Chang-Jiun Wu & Gerald C. Chu & Yonghong Xiao & Dennis Ho & Jingfang Zhang & Samuel R. Perry & Emma S. Labrot & Xiaoqiu Wu & Rosina Lis & Yujin Hoshida & David Hiller & Baoli Hu & Shan Ji, 2011. "SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression," Nature, Nature, vol. 470(7333), pages 269-273, February.
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