Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype.
Int J Cancer
; 146(11): 3065-3076, 2020 06 01.
Article
em En
| MEDLINE
| ID: mdl-32017074
ABSTRACT
Highly tumorigenic, drug-resistant cancer stem-like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem-like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility. Most differential chromatin accessibility was independent of methylation and affected the expression of driver genes such as E2F3, a cell cycle regulator associated with aggressive bladder cancer. Cancer stem-like cells exhibited increased E2F3 promoter accessibility and increased E2F3 expression that drove cell migration, invasiveness and drug resistance. Epigenetic interference using a DNA methylation inhibitor blocked the transition to a cancer stem-like state and reduced E2F3 expression. Our findings indicate that epigenetic plasticity plays a key role in the transition to and from an aggressive, drug-resistant phenotype.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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Neoplasias da Bexiga Urinária
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Metilação de DNA
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Fator de Transcrição E2F3
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Plasticidade Celular
Limite:
Humans
Idioma:
En
Revista:
Int J Cancer
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Canadá