ZBTB18 restricts chromatin accessibility and prevents transcriptional adaptations that drive metastasis.
Sci Adv
; 9(1): eabq3951, 2023 01 06.
Article
em En
| MEDLINE
| ID: mdl-36608120
ABSTRACT
Metastases arise from rare cancer cells that successfully adapt to the diverse microenvironments encountered during dissemination through the bloodstream and colonization of distant tissues. How cancer cells acquire the ability to appropriately respond to microenvironmental stimuli remains largely unexplored. Here, we report an epigenetic pliancy mechanism that allows cancer cells to successfully metastasize. We find that a decline in the activity of the transcriptional repressor ZBTB18 defines metastasis-competent cancer cells in mouse models. Restoration of ZBTB18 activity reduces chromatin accessibility at the promoters of genes that drive metastasis, such as Tgfbr2, and this prevents TGFß1 pathway activation and consequently reduces cell migration and invasion. Besides repressing the expression of metastatic genes, ZBTB18 also induces widespread chromatin closing, a global epigenetic adaptation previously linked to reduced phenotypic flexibility. Thus, ZBTB18 is a potent chromatin regulator, and the loss of its activity enhances chromatin accessibility and transcriptional adaptations that promote the phenotypic changes required for metastasis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Repressoras
/
Cromatina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Sci Adv
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos