Genome-wide chromatin accessibility analysis in colorectal cancer PDC (ATAC-Seq)

Transcriptional reactivation of hTERT is the limiting step in tumorigenesis. While mutations in hTERT promoter in 19% of cancers are recognized as key drivers of hTERT reactivation, mechanisms by which wildtype hTERT (WT-hTERT) promoter is reactivated, in majority of human cancers, remain unknown. Using primary colorectal cancers (CRC) we identify, Tert INTeracting region 2 (T-INT2), the critical chromatin region essential for reactivating WT-hTERT promoter in CRCs. T-INT2 is essential for the formation of a unique chromatin architecture needed for the reactivation of WT-hTERT. This cancer-cell-specific WT-hTERT reactivation is mediated by -catenin and JunD signalling via T-INT2. Pharmacological screens uncovered Salinomycin, which inhibits WT-hTERT reactivation by blocking T-INT2 mediated formation of chromatin architecture essential for WT-hTERT promoter reactivation. Our results provide a framework for therapeutic targeting of WT-hTERT, specifically in cancer cells and explain, for the first time how known CRC alterations, such as APC lead to WT-hTERT promoter reactivation during oncogene-induced stepwise-transformation. 6 Primary colon cancer cells were analyzed using ATAC-seq. Each cells include 2 replicates.