A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer
Yanli Liu, Zhong Wu, Jin Zhou, Dinesh K. A. Ramadurai, Katelyn L. Mortenson, Estrella Aguilera-Jimenez, Yifei Yan, Xiaojun Yang, Alison M. Taylor, Katherine E. Varley, Jason Gertz, Peter S. Choi, Andrew D. Cherniack, Xingdong Chen, Adam J. Bass, Swneke D. Bailey, Xiaoyang Zhang
Abstract
Amplification and overexpression of the SOX2 oncogene represent a hallmark of squamous cancers originating from diverse tissue types. Here, we find that squamous cancers selectively amplify a 3' noncoding region together with SOX2, which harbors squamous cancer-specific chromatin accessible regions. We identify a single enhancer e1 that predominantly drives SOX2 expression. Repression of e1 in SOX2-high cells causes collapse of the surrounding enhancers, remarkable reduction in SOX2 expression, and a global transcriptional change reminiscent of SOX2 knockout. The e1 enhancer is driven by a combination of transcription factors including SOX2 itself and the AP-1 complex, which facilitates recruitment of the co-activator BRD4. CRISPR-mediated activation of e1 in SOX2-low cells is sufficient to rebuild the e1-SOX2 loop and activate SOX2 expression. Our study shows that squamous cancers selectively amplify a predominant enhancer to drive SOX2 overexpression, uncovering functional links among enhancer activation, chromatin looping, and lineage-specific copy number amplifications of oncogenes.