Reference - Detail
| RRC ID | 85988 |
|---|---|
| Author | Li J, Huang K, Thakur M, McBride F, Sadagopan A, Gallant DS, Khanna P, Laimon YN, Li B, Mohanna R, Ge M, Weiss CN, Achom M, Xu Q, Matar S, Lee GM, Huang K, Gui M, Wu CL, Cornejo KM, Choueiri TK, Ryback BA, Signoretti S, Bar-Peled L, Viswanathan SR. |
| Title | Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma. |
| Journal | Nat Metab |
| Abstract |
Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic nature of most other renal cancers. Reliance on this TFE3 fusion-driven OXPHOS programme renders tRCCs vulnerable to NADH reductive stress, a metabolic stress induced by an imbalance of reducing equivalents. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to this metabolic state, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1 compromises tRCC cell growth by stabilizing HIF-1α and promoting metabolic reprogramming away from OXPHOS, thus representing a vulnerability for OXPHOS-dependent tRCC cells. Our study defines tRCC as being dependent on a mitochondria-centred metabolic programme driven by TFE3 fusions and nominates EGLN1 inhibition as a therapeutic strategy in this cancer. |
| Volume | 7(3) |
| Pages | 478-492 |
| Published | 2025-3-1 |
| DOI | 10.1038/s42255-025-01218-9 |
| PII | 10.1038/s42255-025-01218-9 |
| PMID | 39915638 |
| MeSH | Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors* / metabolism Carcinoma, Renal Cell* / genetics Carcinoma, Renal Cell* / metabolism Carcinoma, Renal Cell* / pathology Cell Line, Tumor Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism Kidney Neoplasms* / genetics Kidney Neoplasms* / metabolism Kidney Neoplasms* / pathology Mice Mitochondria / metabolism Oxidative Phosphorylation* Translocation, Genetic |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | X(Twitter) |
| Total number of mentions | 12 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | S-TFE(RCB4699) |