Systematic Discovery and Therapeutic Targeting of Pro-growth Enhancers in Human Cancer Cells [PLAC-seq]

Precision medicine depends critically on the development of treatment strategies that can specifically target cancer cells and have minimal adverse effects on normal cells. Cancer-cell-specific enhancers represent a class of therapeutic targets, however, a lack of comprehensive map of pro-growth enhancers in cancer cells presents a significant hurdle to this strategy. Here we address the knowledge gap by carrying out large-scale CRISPR-based perturbation screens to identify pro-growth enhancers in multiple cancer cell lines. We report the finding of 510 pro-growth enhancers, the majority of which show evidence of accessibility only in cancer cells but not in normal cell types. In addition, 16 pro-growth enhancers are selectively associated with poor clinical outcomes in colorectal cancer. These cancer cell specific pro-growth enhancers are modulated by lineage-specific transcription factors acting downstream of signaling pathways, and could be pharmacologically targeted in specific cancer cell types. Our results not only uncover the molecular mechanism governing the function of cancer cell-specific pro-growth enhancers but also reveal novel therapeutic targets for cancer treatment. Examination of chromatin interactions in multiple cancer cell lines