Switch of ELF3 and ATF4 transcriptional axis programs the amino acid insufficiency-linked epithelial-to-mesenchymal transition.
Mol Ther
; 32(6): 1956-1969, 2024 Jun 05.
Article
in En
| MEDLINE
| ID: mdl-38627967
ABSTRACT
Epithelial-to-mesenchymal transition (EMT) that endows cancer cells with increased invasive and migratory capacity enables cancer dissemination and metastasis. This process is tightly associated with metabolic reprogramming acquired for rewiring cell status and signaling pathways for survival in dietary insufficiency conditions. However, it remains largely unclear how transcription factor (TF)-mediated transcriptional programs are modulated during the EMT process. Here, we reveal that depletion of a key epithelial TF, ELF3 (E74-like factor-3), triggers a transforming growth factor ß (TGF-ß) signaling activation-like mesenchymal transcriptomic profile and metastatic features linked to the aminoacyl-tRNA biogenesis pathway. Moreover, the transcriptome alterations elicited by ELF3 depletion perfectly resemble an ATF4-dependent weak response to amino acid starvation. Intriguingly, we observe an exclusive enrichment of ELF3 and ATF4 in epithelial and TGF-ß-induced or ELF3-depletion-elicited mesenchymal enhancers, respectively, with rare co-binding on altered enhancers. We also find that the upregulation of aminoacyl-tRNA synthetases and some mesenchymal genes upon amino acid deprivation is diminished in ATF4-depleted cells. In sum, the loss of ELF3 binding on epithelial enhancers and the gain of ATF4 binding on the enhancers of mesenchymal factors and amino acid deprivation responsive genes facilitate the loss of epithelial cell features and the gain of TGF-ß-signaling-associated mesenchymal signatures, which further promote lung cancer cell metastasis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
/
Gene Expression Regulation, Neoplastic
/
Transforming Growth Factor beta
/
DNA-Binding Proteins
/
Activating Transcription Factor 4
/
Epithelial-Mesenchymal Transition
/
Amino Acids
Limits:
Animals
/
Humans
Language:
En
Journal:
Mol Ther
/
Mol. ther
/
Molecular therapy
Journal subject:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Estados Unidos