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BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma

Author

Listed:
  • Chengheng Liao

    (University of Texas Southwestern Medical Center)

  • Lianxin Hu

    (University of Texas Southwestern Medical Center
    Zhejiang University)

  • Liwei Jia

    (University of Texas Southwestern Medical Center)

  • Jin Zhou

    (University of Texas Southwestern Medical Center)

  • Tao Wang

    (University of Texas Southwestern Medical Center)

  • Kangsan Kim

    (University of Texas Southwestern Medical Center)

  • Hua Zhong

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Hongwei Yao

    (University of Texas Southwestern Medical Center)

  • Lei Dong

    (University of Texas Southwestern Medical Center)

  • Lei Guo

    (University of Texas Southwestern Medical Center)

  • Qian Liang

    (University of Texas Southwestern Medical Center)

  • Cheng Zhang

    (University of Texas Southwestern Medical Center)

  • Fangzhou Zhao

    (University of Texas Southwestern Medical Center)

  • Jun Fang

    (University of Texas Southwestern Medical Center)

  • Hongyi Liu

    (University of Texas Southwestern Medical Center)

  • Shina Li

    (University of Texas Southwestern Medical Center)

  • Lin Xu

    (University of Texas Southwestern Medical Center)

  • Jeremy M. Simon

    (Dana-Farber Cancer Institute
    Harvard T.H. Chan School of Public Health)

  • Srinivas Malladi

    (University of Texas Southwestern Medical Center)

  • Payal Kapur

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • James Brugarolas

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Ralph J. DeBerardinis

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Qing Zhang

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Clear cell renal cell carcinoma (ccRCC), a metabolic disease originating from renal proximal convoluted tubule (PCT) epithelial cells, remains incompletely understood in terms of its initiating signaling events. Here, we identify γ-butyrobetaine hydroxylase 1 (BBOX1), a key enzyme in carnitine synthesis predominantly expressed in PCT cells, as a tumor suppressor in ccRCC. BBOX1 expression is lost during ccRCC malignant transformation, and its restoration reduces cell viability in physiological medium and inhibits xenograft tumor growth. Transcriptomic analyses reveal that BBOX1 suppresses critical metabolic pathways including mTORC1 signaling and glycolysis in ccRCC. Further, we identify TANK-binding kinase 1 (TBK1) as an essential mediator of mTORC1 and glycolysis activation and as a target of BBOX1-mediated tumor suppression. Mechanistically, BBOX1 disrupts TBK1 activation by preventing its interaction with the upstream activator doublecortin-like kinase 2 (DCLK2). This BBOX1-DCLK2-TBK1 axis unveils an important mechanism in ccRCC metabolic dysregulation and highlights potential therapeutic strategies.

Suggested Citation

  • Chengheng Liao & Lianxin Hu & Liwei Jia & Jin Zhou & Tao Wang & Kangsan Kim & Hua Zhong & Hongwei Yao & Lei Dong & Lei Guo & Qian Liang & Cheng Zhang & Fangzhou Zhao & Jun Fang & Hongyi Liu & Shina Li, 2025. "BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56955-y
    DOI: 10.1038/s41467-025-56955-y
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    1. Kangsan Kim & Qinbo Zhou & Alana Christie & Christina Stevens & Yuanqing Ma & Oreoluwa Onabolu & Suneetha Chintalapati & Tiffani Mckenzie & Vanina Toffessi Tcheuyap & Layton Woolford & He Zhang & Nirm, 2021. "Determinants of renal cell carcinoma invasion and metastatic competence," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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