2. Academic Validation
  3. BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma

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

  • Nat Commun. 2025 Feb 11;16(1):1543. doi: 10.1038/s41467-025-56955-y.
Chengheng Liao # 1,  Lianxin Hu # 2 3,  Liwei Jia 2,  Jin Zhou 2,  Tao Wang 2,  Kangsan Kim 2,  Hua Zhong 2 4,  Hongwei Yao 2,  Lei Dong 5,  Lei Guo 5,  Qian Liang 2,  Cheng Zhang 2,  Fangzhou Zhao 2,  Jun Fang 2,  Hongyi Liu 2,  Shina Li 2,  Lin Xu 5,  Jeremy M Simon 6 7,  Srinivas Malladi 2,  Payal Kapur 2 8,  James Brugarolas 8 9,  Ralph J DeBerardinis 10 11,  Qing Zhang 12 13
Affiliations

Affiliations

  • 1 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Chengheng.Liao@UTSouthwestern.edu.
  • 2 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Urology, Institute of Urologic Science and Technology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 4 Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 5 Quantitative Biomedical Research Center, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 8 Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 9 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 10 Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 11 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 12 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Qing.Zhang@UTSouthwestern.edu.
  • 13 Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. Qing.Zhang@UTSouthwestern.edu.
  • # Contributed equally.
PMID: 39934163 DOI: 10.1038/s41467-025-56955-y
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.

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