The CtIP-CtBP1/2-HDAC1-AP1 transcriptional complex is required for the transrepression of DNA damage modulators in the pathogenesis of osteosarcoma.
Transl Oncol
; 21: 101429, 2022 Jul.
Article
em En
| MEDLINE
| ID: mdl-35452995
Most tumors, including osteosarcomas, have deficiencies in DNA damage repair. However, the regulatory mechanisms underlying dysregulation of DNA damage repair genes are still being investigated. In this study, we reveal that C-terminal binding protein (CtBP) interacting protein (CtIP) couples with three transcriptional regulators, CtBP1/2 heterodimer, histone deacetylase 1 (HDAC1), and two subunits of the activating protein 1 (AP1) transcription factor to assemble a transcriptional complex. This complex specifically controls the expression of four genes involved in DNA damage and repair processes: MutL homolog 1 (MLH1), MutS Homolog 3 (MSH3), breast cancer type 1 (BRCA1), and cyclin dependent kinase inhibitor 1A (CDKN1A). Chromatin immunoprecipitation (ChIP) assay results revealed that the CtIP-CtBP1/2-HDAC1-AP1 complex regulated these four genes by binding to their promoters through the TGAT/CTCA consensus sequence. The depletion of CtIP, CtBP1/2, and HDAC1 increased the expression levels of MLH1, MSH3, BRCA1, and CDKN1A and inhibited in vitro and in vivo osteosarcoma cell growth. Overexpression of MLH1, MSH3, BRCA1, or CDKN1A in osteosarcoma cells can reduce cell viability, colony formation, cell migration, and tumor growth. Our findings suggest that the CtIP-CtBP1/2-HDAC1-AP1 complex is required for mediation of DNA damage processes for the pathogenesis of osteosarcoma.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Etiology_studies
Idioma:
En
Revista:
Transl Oncol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Estados Unidos