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Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma

Author

Listed:
  • Emma Martell

    (University of Manitoba
    University of Manitoba)

  • Helgi Kuzmychova

    (University of Manitoba)

  • Esha Kaul

    (University of Manitoba)

  • Harshal Senthil

    (University of Manitoba)

  • Subir Roy Chowdhury

    (CancerCare Manitoba)

  • Ludivine Coudière Morrison

    (University of Manitoba)

  • Agnes Fresnoza

    (University of Manitoba)

  • Jamie Zagozewski

    (University of Manitoba)

  • Chitra Venugopal

    (McMaster University
    McMaster University)

  • Chris M. Anderson

    (Health Sciences Centre
    University of Manitoba)

  • Sheila K. Singh

    (McMaster University
    McMaster University
    McMaster University)

  • Versha Banerji

    (CancerCare Manitoba
    University of Manitoba
    University of Manitoba
    CancerCare Manitoba)

  • Tamra E. Werbowetski-Ogilvie

    (University of Manitoba
    CancerCare Manitoba)

  • Tanveer Sharif

    (University of Manitoba
    University of Manitoba
    CancerCare Manitoba)

Abstract

Group 3 medulloblastoma (G3 MB) carries the worst prognosis of all MB subgroups. MYC oncoprotein is elevated in G3 MB tumors; however, the mechanisms that support MYC abundance remain unclear. Using metabolic and mechanistic profiling, we pinpoint a role for mitochondrial metabolism in regulating MYC. Complex-I inhibition decreases MYC abundance in G3 MB, attenuates the expression of MYC-downstream targets, induces differentiation, and prolongs male animal survival. Mechanistically, complex-I inhibition increases inactivating acetylation of antioxidant enzyme SOD2 at K68 and K122, triggering the accumulation of mitochondrial reactive oxygen species that promotes MYC oxidation and degradation in a mitochondrial pyruvate carrier (MPC)-dependent manner. MPC inhibition blocks the acetylation of SOD2 and oxidation of MYC, restoring MYC abundance and self-renewal capacity in G3 MB cells following complex-I inhibition. Identification of this MPC-SOD2 signaling axis reveals a role for metabolism in regulating MYC protein abundance that has clinical implications for treating G3 MB.

Suggested Citation

  • Emma Martell & Helgi Kuzmychova & Esha Kaul & Harshal Senthil & Subir Roy Chowdhury & Ludivine Coudière Morrison & Agnes Fresnoza & Jamie Zagozewski & Chitra Venugopal & Chris M. Anderson & Sheila K. , 2023. "Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma," Nature Communications, Nature, vol. 14(1), pages 1-26, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38049-9
    DOI: 10.1038/s41467-023-38049-9
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    References listed on IDEAS

    as
    1. Liam D. Hendrikse & Parthiv Haldipur & Olivier Saulnier & Jake Millman & Alexandria H. Sjoboen & Anders W. Erickson & Winnie Ong & Victor Gordon & Ludivine Coudière-Morrison & Audrey L. Mercier & Moha, 2022. "Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation," Nature, Nature, vol. 612(7940), pages 12-12, December.
    2. Yu Chen Feng & Xiao Ying Liu & Liu Teng & Qiang Ji & Yongyan Wu & Jin Ming Li & Wei Gao & Yuan Yuan Zhang & Ting La & Hessam Tabatabaee & Xu Guang Yan & M. Fairuz B. Jamaluddin & Didi Zhang & Su Tang , 2020. "c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. Liam D. Hendrikse & Parthiv Haldipur & Olivier Saulnier & Jake Millman & Alexandria H. Sjoboen & Anders W. Erickson & Winnie Ong & Victor Gordon & Ludivine Coudière-Morrison & Audrey L. Mercier & Moha, 2022. "Failure of human rhombic lip differentiation underlies medulloblastoma formation," Nature, Nature, vol. 609(7929), pages 1021-1028, September.
    4. Jiska Reest & Sergio Lilla & Liang Zheng & Sara Zanivan & Eyal Gottlieb, 2018. "Proteome-wide analysis of cysteine oxidation reveals metabolic sensitivity to redox stress," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    5. Jamie Zagozewski & Ghazaleh M. Shahriary & Ludivine Coudière Morrison & Olivier Saulnier & Margaret Stromecki & Agnes Fresnoza & Gareth Palidwor & Christopher J. Porter & Antoine Forget & Olivier Ayra, 2020. "An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
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