Potential role of ZEB1 as a DNA repair regulator in colorectal cancer cells revealed by cancer-associated promoter profiling.
Oncol Rep
; 38(4): 1941-1948, 2017 Oct.
Article
em En
| MEDLINE
| ID: mdl-28791382
ABSTRACT
Besides being a key contributor to epithelialtomesenchymal transition (EMT) activation and stemness maintenance, zinc finger E-box binding homeobox 1 (ZEB1) is also a crucial inducer of chemoresistance and radioresistance. Unlike the clear mechanism that mediates its effect on EMT and dedifferentiation, the mechanism of how ZEB1 promotes chemo- and radio-resistance remains to be elucidated. It has been previously reported that ZEB1 promotes DNA double-strand break clearance by enhancing the deubiquitylating activity of ubiquitin-specific peptidase (USP)7 on checkpoint kinase 1, which is an important step during DNA repair. It was hypothesized that as a transcriptional suppressor, ZEB1 may be involved in an unbalanced DNA damage response (DDR) by affecting other key components. Therefore, in the present study, the target gene occupancy of ZEB1 was mapped in colorectal cancer cells using the ChIP-on-chip method, revealing positive intervals enriched along the three DDR-associated genes USP17, chromodomain helicase DNA-binding protein 1-like and double homeobox 4. The E-boxes identified in the binding regions and the enhanced mRNA expression of the three genes following the knockdown of ZEB1 supported the identification of these three genes as downstream target genes of ZEB1. Furthermore, ZEB1 knockdown initiated a chemosensitization effect, induced G1/S arrest and increased apoptosis, which functionally validated the three ZEB1 downstream targets. In summary, the present study identified three DDR-associated genes as ZEB1 downstream targets, and demonstrated that their suppression by ZEB1 contributes to ZEB1-mediated chemoresistance.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Reparo do DNA
/
Homeobox 1 de Ligação a E-box em Dedo de Zinco
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Oncol Rep
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2017
Tipo de documento:
Article