Epigenetic misactivation of a distal developmental enhancer cluster drives SOX2 overexpression in breast and lung cancer

Enhancer reprogramming has been proposed as a major source of gene expression dysregulation during tumorigenesis. Here, we identify SOX2 developmental enhancers that are misactivated in breast and lung carcinoma. Deletion of the SRR124–134 enhancer cluster disrupts SOX2 transcription and genome-wide chromatin accessibility in cancer cells. ATAC- and RNA-seq analysis of primary tumors shows that chromatin accessibility at this cluster is correlated with SOX2 overexpression in breast and lung cancer. We further identify FOXA1 as an activator and NFIB as a repressor of SRR124–134 activity and SOX2 transcription. Notably, the conserved SRR124 and SRR134 regions are essential during mouse development, where homozygous deletion results in the lethal failure of esophageal-tracheal separation. Our findings indicate that the SRR124–134 enhancer cluster drives SOX2 expression during development. In breast and lung cancer, FOXA1-induced aberrant activity of the SRR124–134 cluster drives SOX2 overexpression, demonstrating how developmental enhancers can be recommissioned during tumorigenesis. These results highlight the importance of understanding enhancer dynamics during development and disease while also providing new opportunities for therapeutic intervention by targeting aberrantly activated developmental enhancers. ### Competing Interest Statement The authors have declared no competing interest.