Chemotherapy suppresses SHH gene expression via a specific enhancer.
J Genet Genomics
; 50(1): 27-37, 2023 01.
Article
em En
| MEDLINE
| ID: mdl-35998878
ABSTRACT
Sonic hedgehog (SHH) signaling is a key regulator of embryonic development and tissue homeostasis that is involved in gastrointestinal (GI) cancer progression. Regulation of SHH gene expression is a paradigm of long-range enhancer function. Using the classical chemotherapy drug 5-fluorouracil (5FU) as an example, here we show that SHH gene expression is suppressed by chemotherapy. SHH is downstream of immediate early genes (IEGs), including Early growth response 1 (Egr1). A specific 139 kb upstream enhancer is responsible for its down-regulation. Knocking down EGR1 expression or blocking its binding to this enhancer renders SHH unresponsive to chemotherapy. We further demonstrate that down-regulation of SHH expression does not depend on 5FU's impact on nucleotide metabolism or DNA damage; rather, a sustained oxidative stress response mediates this rapid suppression. This enhancer is present in a wide range of tumors and normal tissues, thus providing a target for cancer chemotherapy and its adverse effects on normal tissues. We propose that SHH is a stress-responsive gene downstream of IEGs, and that traditional chemotherapy targets a specific enhancer to suppress its expression.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Elementos Facilitadores Genéticos
/
Proteínas Hedgehog
Idioma:
En
Revista:
J Genet Genomics
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
CHINA
/
CN
/
REPUBLIC OF CHINA