Faculty, Staff and Student Publications

Language

English

Publication Date

2-11-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-56955-y

PMID

39934163

PMCID

PMC11814379

PubMedCentral® Posted Date

2-11-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Carcinoma, Renal Cell, gamma-Butyrobetaine Dioxygenase, Kidney Tubules, Proximal, Down-Regulation, Gene Expression Regulation, Neoplastic, Carcinogenesis, Cell Survival, Glucose, Glutamine, Genes, Tumor Suppressor, Signal Transduction, Cell Line, Tumor, Humans, Kidney Neoplasms, Protein Serine-Threonine Kinases, Glycolysis, Male, Female, Animals, Mice, Tumour-suppressor proteins, Cancer metabolism, Tumour-suppressor proteins, Renal cell carcinoma

Published Open-Access

yes

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