Genome-scale CRISPR-Cas9 screen of Wnt/β-catenin signaling identifies therapeutic targets for colorectal cancer.
Chunhua WanSylvia MaharaClaire SunAnh DoanHui Kheng ChuaDakang XuJia BianYue LiDanxi ZhuDhanya SoorajTomasz CierpickiJolanta GrembeckaRon FiresteinPublished in: Science advances (2021)
Aberrant activation of Wnt/β-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/β-catenin signaling in CRC cells. We found marked discrepancies between the artificial TOP reporter activity and β-catenin-mediated endogenous transcription and redundant roles of T cell factor/lymphoid enhancer factor transcription factors in transducing β-catenin signaling. Compiled functional genomic screens and network analysis revealed unique epigenetic regulators of β-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 β-catenin to consensus DNA motifs and the transcription of β-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 β-catenin-driven malignancies.
Keyphrases
- transcription factor
- cell proliferation
- crispr cas
- genome wide
- epithelial mesenchymal transition
- network analysis
- dna methylation
- genome editing
- gene expression
- dna binding
- high throughput
- stem cells
- single cell
- acute myeloid leukemia
- copy number
- induced apoptosis
- cell death
- genome wide identification
- small molecule
- single molecule
- oxidative stress
- circulating tumor
- heat shock
- cell free