Genome-scale CRISPR-Cas9 screen of Wnt/ß-catenin signaling identifies therapeutic targets for colorectal cancer.
Sci Adv
; 7(21)2021 05.
Article
em En
| MEDLINE
| ID: mdl-34138730
ABSTRACT
Aberrant activation of Wnt/ß-catenin pathway is a key driver of colorectal cancer (CRC) growth and of great therapeutic importance. In this study, we performed comprehensive CRISPR screens to interrogate the regulatory network of Wnt/ß-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and ß-catenin-mediated endogenous transcription and redundant roles of T cell factor/lymphoid enhancer factor transcription factors in transducing ß-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of ß-catenin transcriptional output, including the histone lysine methyltransferase 2A oncoprotein (KMT2A/Mll1). Using an integrative epigenomic and transcriptional profiling approach, we show that KMT2A loss diminishes the binding of ß-catenin to consensus DNA motifs and the transcription of ß-catenin targets in CRC. These results suggest that KMT2A may be a promising target for CRCs and highlight the broader potential for exploiting epigenetic modulation as a therapeutic strategy for ß-catenin-driven malignancies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Beta Catenina
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Austrália