State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Nat Commun. 2021 Dec 8;12(1):7139. doi: 10.1038/s41467-021-27055-4.
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.
SOX2 癌基因的扩增和过表达是源自多种组织类型的鳞状细胞癌的一个显著特征。在这里，我们发现鳞状细胞癌选择性地扩增了一个与 SOX2 一起的 3'非编码区，该区域包含鳞状癌细胞特异性的染色质可及区域。我们鉴定出一个单一的增强子 e1，它主要驱动 SOX2 的表达。在 SOX2 高表达的细胞中抑制 e1 会导致周围增强子的崩溃，SOX2 表达的显著减少，以及类似于 SOX2 敲除的全局转录变化。e1 增强子由包括 SOX2 本身和 AP-1 复合物在内的转录因子组合驱动，这有助于募集共激活因子 BRD4。CRISPR 介导的 e1 在 SOX2 低表达细胞中的激活足以重建 e1-SOX2 环并激活 SOX2 表达。我们的研究表明，鳞状细胞癌选择性地扩增主要的增强子来驱动 SOX2 的过表达，揭示了增强子激活、染色质环化和癌基因的谱系特异性拷贝数扩增之间的功能联系。
