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HIF1a Plays a Crucial Role in the Development of TFE3-Rearranged Renal Cell Carcinoma by Orchestrating a Metabolic Shift Toward Fatty Acid Synthesis

  1. Author:
    Nishizawa, Hidekazu
    Funasaki, Shintaro
    Ma, Wenjuan
    Kubota, Yoshiaki
    Watanabe, Kazuhide
    Arima, Yuichiro
    Kuroda, Shoichiro
    Ito, Takaaki
    Furuya, Mitsuko
    Motoshima, Takanobu
    Nishiyama, Akira
    Mehanna, Sally
    Satou, Yorifumi
    Hasumi, Hisashi
    Jikuya, Ryosuke
    Makiyama, Kazuhide
    Tamura, Tomohiko
    Oike, Yuichi
    Tanaka, Yasuhito
    Suda, Toshio
    Schmidt,Laura
    Linehan, W Marston
    Baba, Masaya [ORCID]
    Kamba, Tomomi

  2. Author Address

    Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto, Japan., Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Department of Anatomy, Institute for Advanced Medical Research and Keio University School of Medicine, Tokyo, Japan., RIKEN Center for Integrative Medical Sciences, Yokohama, Japan., Developmental Cardiology Laboratory, International Research Center for Medical Science (IRCMS), Kumamoto University, Kumamoto, Japan., Department of Medical Technology, Kumamoto Health Science University Faculty of Health Sciences, Kumamoto, Japan., Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan., Department of Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan., Biotechnology Department, Faculty of Nanotechnology for Postgraduate Studies, Cairo University, Ad Doqi, Egypt., Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan., Department of Urology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan., Advanced Medical Research Center, Yokohama City University, Kanagawa, Japan., Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Laboratory of Stem Cell Regulation, International Research Center for Medical Science (IRCMS), Kumamoto University, Kumamoto, Japan., Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.,
    1. Year: 2025
    2. Date: Jan
  2. Journal: Genes to Cells : devoted to molecular & cellular mechanisms
    1. 30
    2. 1
    3. Pages: e13195
  4. Type of Article: Article
  5. Article Number: e13195
  1. Abstract:

    Tumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3-rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1a and HIF2a. The upregulation of HIF1a by PRCC-TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3-RCC mouse models with Hif1a and/or Hif2a knockout mice and found that Hif1a, rather than Hif2a, is essential for tumor development in vivo. RNA-seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1a/SREBP1-dependent mechanism in TFE3-RCC. Our data suggest that the coordinated metabolic shift via the PRCC-TFE3/HIF1a/SREBP1 axis is a key mechanism by which PRCC-TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3-RCC. © 2025 The Author(s). Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

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  2. DOI: 10.1111/gtc.13195
  3. PMID: 39807625
  4. PMCID: PMC11729263

Library Notes

  1. Fiscal Year: FY2024-2025
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