eIF4B enhances ATF4 expression and contributes to cellular adaptation to asparagine limitation in BRAF-mutated A375 melanoma.
Biochem Biophys Res Commun
; 573: 93-99, 2021 10 08.
Article
en En
| MEDLINE
| ID: mdl-34403810
ABSTRACT
ATF4 is a crucial transcription factor in the integrated stress response, a major adaptive signaling pathway activated by tumor microenvironment and therapeutic stresses. BRAF inhibitors, such as vemurafenib, induce ATF4 in BRAF-mutated melanoma cells, but the mechanisms of ATF4 induction are not fully elucidated. Here, we show that ATF4 expression can be upregulated by eukaryotic initiation factor 4B (eIF4B) in BRAF-mutated A375 cells. Indeed, eIF4B knockout (KO) prevented ATF4 induction and activation of the uORF-mediated ATF4 translation mechanism during vemurafenib treatment, which were effectively recovered by the rescue of eIF4B. Transcriptome analysis revealed that eIF4B KO selectively influenced ATF4-target gene expression among the overall gene expression changed by vemurafenib. Interestingly, eIF4B supported cellular proliferation under asparagine-limited conditions, possibly through the eIF4B-ATF4 pathway. Our findings indicate that eIF4B can regulate ATF4 expression, thereby contributing to cellular stress adaptation, which could be targeted as a therapeutic approach against malignancies, including melanoma.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Asparagina
/
Factores Eucarióticos de Iniciación
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Proteínas Proto-Oncogénicas B-raf
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Factor de Transcripción Activador 4
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Melanoma
Límite:
Humans
Idioma:
En
Año:
2021
Tipo del documento:
Article