Focal Amplification of Super-Enhancers Upregulates Oncogenic Drivers

Copy-number alterations are important drivers of cancer; however, the specific mechanisms by which amplifications and deletions in noncoding regions promote cancer are not understood. By analyzing The Cancer Genome Atlas copy-number data and corresponding acetylated histone H3 lysine 27 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data across 29 tumor types, Zhang, Choi, Francis, and colleagues identified 55 focally amplified noncoding regions, 6 of which were tissue-specific amplifications in super-enhancer regions. In head and neck squamous cell carcinoma, KLF5 was upregulated by amplification of a cluster of 3 super-enhancers marked by H3K27ac. Esophageal carcinomas harbored amplification of a distinct KLF5 super-enhancer, further supporting super-enhancer amplification as a mechanism to upregulate putative oncogenes including KLF5. Focal amplification of USP12 and PARD6B super-enhancers occurred in colorectal carcinoma and liver hepatocellular carcinoma, respectively. In addition, two distinct noncoding focal amplifications located 3′ of the MYC gene and associated with increased MYC expression were found in lung adenocarcinoma (MYC-LASE) and uterine corpus endometrial carcinoma (MYC-ECSE), and were in different regions than the previously identified MYC super-enhancers in T-cell acute lymphoblastic leukemia and acute myeloid leukemia. H3K27ac and p300 ChIP-seq confirmed that the MYC-LASE and MYC-ECSE super-enhancers were active only in cell lines of the respective tumor type, and chromosome conformation capture demonstrated that both super-enhancers physically interacted with the MYC promoter only in cells in which the super-enhancers were active. The active enhancer region of MYC-LASE was mapped to a 148bp region with the strongest activity in reporter assays, which required binding by the transcription factors NFE2L2 and CEBPβ for optimal activation. CRISPR/Cas9–mediated repression or deletion of the MYC-LASE active enhancer region reduced MYC expression and anchorage-independent growth. These findings suggest that amplification of super-enhancers can upregulate oncogenes in a lineage-specific manner to promote tumorigenesis.

Zhang X, Choi PS, Francis JM, Imielinski M, Watanabe H, Cherniack AD, et al. Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat Genet 2015 Dec 14 [Epub ahead of print].

• ©2016 American Association for Cancer Research.