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Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase

Author

Listed:
  • Rin Mizuno

    (Kyoto University
    Kyoto University Graduate School of Medicine)

  • Hiroaki Hojo

    (Kyoto University
    Advanced Telecommunications Research Institute International (ATR)
    Japan Science and Technology Agency (JST))

  • Masatomo Takahashi

    (Kyushu University)

  • Soshiro Kashio

    (The University of Tokyo)

  • Sora Enya

    (Advanced Telecommunications Research Institute International (ATR)
    Japan Science and Technology Agency (JST))

  • Motonao Nakao

    (Kyushu University)

  • Riyo Konishi

    (Kyoto University)

  • Mayuko Yoda

    (Kyoto University)

  • Ayano Harata

    (Kyoto University)

  • Junzo Hamanishi

    (Kyoto University Graduate School of Medicine)

  • Hiroshi Kawamoto

    (Kyoto University)

  • Masaki Mandai

    (Kyoto University Graduate School of Medicine)

  • Yutaka Suzuki

    (The University of Tokyo)

  • Masayuki Miura

    (The University of Tokyo)

  • Takeshi Bamba

    (Kyushu University)

  • Yoshihiro Izumi

    (Kyushu University)

  • Shinpei Kawaoka

    (Kyoto University
    Advanced Telecommunications Research Institute International (ATR)
    Japan Science and Technology Agency (JST)
    Tohoku University)

Abstract

Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis.

Suggested Citation

  • Rin Mizuno & Hiroaki Hojo & Masatomo Takahashi & Soshiro Kashio & Sora Enya & Motonao Nakao & Riyo Konishi & Mayuko Yoda & Ayano Harata & Junzo Hamanishi & Hiroshi Kawamoto & Masaki Mandai & Yutaka Su, 2022. "Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30926-z
    DOI: 10.1038/s41467-022-30926-z
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    References listed on IDEAS

    as
    1. Daniel Kraus & Qin Yang & Dong Kong & Alexander S. Banks & Lin Zhang & Joseph T. Rodgers & Eija Pirinen & Thomas C. Pulinilkunnil & Fengying Gong & Ya-chin Wang & Yana Cen & Anthony A. Sauve & John M., 2014. "Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity," Nature, Nature, vol. 508(7495), pages 258-262, April.
    2. Miki Arai Hojo & Kyoko Masuda & Hiroaki Hojo & Yosuke Nagahata & Keiko Yasuda & Daiya Ohara & Yusuke Takeuchi & Keiji Hirota & Yutaka Suzuki & Hiroshi Kawamoto & Shinpei Kawaoka, 2019. "Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    3. Mark A. Eckert & Fabian Coscia & Agnieszka Chryplewicz & Jae Won Chang & Kyle M. Hernandez & Shawn Pan & Samantha M. Tienda & Dominik A. Nahotko & Gang Li & Ivana Blaženović & Ricardo R. Lastra & Mari, 2019. "Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts," Nature, Nature, vol. 569(7758), pages 723-728, May.
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    Cited by:

    1. Yasushi Kojima & Emi Mishiro-Sato & Teruaki Fujishita & Kiyotoshi Satoh & Rie Kajino-Sakamoto & Isao Oze & Kazuki Nozawa & Yukiya Narita & Takatsugu Ogata & Keitaro Matsuo & Kei Muro & Makoto Mark Tak, 2023. "Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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