Journal
MOLECULAR ONCOLOGY
Volume -, Issue -, Pages -Publisher
WILEY
DOI: 10.1002/1878-0261.13493
Keywords
CRISPR; Cas9; high-throughput screen; MYC; MYC target genes; transcription factor
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The transcription factor MYC plays a crucial role in the development and maintenance of various types of cancer by binding to specific E-box sequences in the genome to regulate gene expression. Through the use of CRISPR/Cas9 technology and high-throughput screening, this study identified essential MYC-regulated genes involved in pathways associated with cancer development. This research provides a novel approach to explore MYC-dependent vulnerabilities in cancer cells, which is of significant importance.
The transcription factor MYC is a proto-oncogene with a well-documented essential role in the pathogenesis and maintenance of several types of cancer. MYC binds to specific E-box sequences in the genome to regulate gene expression in a cell-type- and developmental-stage-specific manner. To date, a combined analysis of essential MYC-bound E-boxes and their downstream target genes important for growth of different types of cancer is missing. In this study, we designed a CRISPR/Cas9 library to destroy E-box sequences in a genome-wide fashion. In parallel, we used the Brunello library to knock out protein-coding genes. We performed high-throughput screens with these libraries in four MYC-dependent cancer cell lines-K562, ST486, HepG2, and MCF7-which revealed several essential E-boxes and genes. Among them, we pinpointed crucial common and cell-type-specific MYC-regulated genes involved in pathways associated with cancer development. Extensive validation of our approach confirmed that E-box disruption affects MYC binding, target-gene expression, and cell proliferation in vitro as well as tumor growth in vivo. Our unique, well-validated tool opens new possibilities to gain novel insights into MYC-dependent vulnerabilities in cancer cells.
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