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Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma

Author

Listed:
  • Do-Won Jeong

    (Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Jong-Wan Park

    (Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Kyeong Seog Kim

    (Seoul National University College of Medicine
    Seoul National University College of Medicine and Hospital)

  • Jiyoung Kim

    (Seoul National University College of Medicine)

  • June Huh

    (Korea University)

  • Jieun Seo

    (Seoul National University College of Medicine
    Seoul National University College of Medicine
    Yokohama National University)

  • Ye Lee Kim

    (Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Joo-Youn Cho

    (Seoul National University College of Medicine
    Seoul National University College of Medicine and Hospital)

  • Kwang-Woong Lee

    (Seoul National University College of Medicine)

  • Junji Fukuda

    (Yokohama National University)

  • Yang-Sook Chun

    (Seoul National University College of Medicine
    Seoul National University College of Medicine
    Seoul National University College of Medicine)

Abstract

Palmitic acid (PA) is the most common fatty acid in humans and mediates palmitoylation through its conversion into palmitoyl coenzyme A. Although palmitoylation affects many proteins, its pathophysiological functions are only partially understood. Here we demonstrate that PA acts as a molecular checkpoint of lipid reprogramming in HepG2 and Hep3B cells. The zinc finger DHHC-type palmitoyltransferase 23 (ZDHHC23) mediates the palmitoylation of plant homeodomain finger protein 2 (PHF2), subsequently enhancing ubiquitin-dependent degradation of PHF2. This study also reveals that PHF2 functions as a tumor suppressor by acting as an E3 ubiquitin ligase of sterol regulatory element-binding protein 1c (SREBP1c), a master transcription factor of lipogenesis. PHF2 directly destabilizes SREBP1c and reduces SREBP1c-dependent lipogenesis. Notably, SREBP1c increases free fatty acids in hepatocellular carcinoma (HCC) cells, and the consequent PA induction triggers the PHF2/SREBP1c axis. Since PA seems central to activating this axis, we suggest that levels of dietary PA should be carefully monitored in patients with HCC.

Suggested Citation

  • Do-Won Jeong & Jong-Wan Park & Kyeong Seog Kim & Jiyoung Kim & June Huh & Jieun Seo & Ye Lee Kim & Joo-Youn Cho & Kwang-Woong Lee & Junji Fukuda & Yang-Sook Chun, 2023. "Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42170-0
    DOI: 10.1038/s41467-023-42170-0
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    References listed on IDEAS

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    1. Shuyang Chen & Bo Zhu & Chengqian Yin & Wei Liu & Changpeng Han & Baoen Chen & Tongzheng Liu & Xin Li & Xiang Chen & Chunying Li & Limin Hu & Jun Zhou & Zhi-Xiang Xu & Xiumei Gao & Xu Wu & Colin R. Go, 2017. "Palmitoylation-dependent activation of MC1R prevents melanomagenesis," Nature, Nature, vol. 549(7672), pages 399-403, September.
    2. Gloria Pascual & Diana Domínguez & Marc Elosúa-Bayes & Felipe Beckedorff & Carmelo Laudanna & Claudia Bigas & Delphine Douillet & Carolina Greco & Aikaterini Symeonidi & Inmaculada Hernández & Sara Ru, 2021. "Dietary palmitic acid promotes a prometastatic memory via Schwann cells," Nature, Nature, vol. 599(7885), pages 485-490, November.
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