Abstract 3363: Enhancer signature profiling identifies novel enhancer clusters for transcription factors in lung cancer
Authors: Tuminello Stephanie , Watanabe Hideo , Sato Takashi 
Published: July 2017

We previously discovered that the targeted focus of the most significant amplicon in squamous cell lung cancer lies on the SOX2 gene locus, a product of which is a critical regulator in specifying squamous cell lineages in the development at dividing foregut to counteract with NKX2-1, which specifies tracheal and later lung lineages and is the most significantly amplified gene in lung adenocarcinoma. Cell lines harboring such amplification from respective lung cancer subtypes are dependent on the expression of these lineage-determining factors for their survival. However, the amplifications of these factors represent only 10-15% of lung cancer, it remains unknown what other lineage programs the remaining majority rely upon. Posttranslational modifications of histone proteins assign different functional regions of the genome, which leads to chromatin states that create stable expression patterns maintaining cellular fates. Studies on genome-wide enhancers have revealed the presence of large enhancer clusters, which are typically enriched in the proximity of lineage factor genes that establish a program defining cellular identity.

To identify novel subsets of lung cancer defined by chromatin modification on lineage-determining factors, we made use of a histone modification marker H3K27Ac, typically present at active enhancers. We profiled H3K27Ac by ChIP-seq in 24 cell lines (14 lung adenocarcinoma, 4 squamous cell carcinoma, 4 small cell lung cancer and 2 breast carcinoma), identifying thousands of active enhancers, i.e. H3K27Ac enriched, and hundreds of super-enhancers (SEs) defined by ROSE algorithm per cell line. As a proof of principle, we found a locus adjacent to NKX2-1 gene as one of the SEs in an NKX2-1-amplified cell line NCI-H3122, suggesting this approach can detect a lineage program that is overridden by cancer cells. We performed unsupervised hierarchical clustering analyses on signals at SEs adjacent to transcriptional regulatory genes and identified unique subsets segregated primarily by their lineages. Several SEs on transcription factors are common between multiple cell lines from the same lineage (e.g., SOX2 and TP63 in squamous cell lineage and NKX2-1 in lung adenocarcinoma lineage). We identified 6 lung adenocarcinoma cell lines that contain SE at the locus of NR4A2, a significantly mutated gene in lung adenocarcinomas, and 2 other lines at the locus of HOPX, a lineage transcription factor for alveolar type I cells. These results suggest that this approach can reveal novel enhancers on lineage factors in a subset of lung cancers.

Note: This abstract was not presented at the meeting.

Citation Format: Stephanie Tuminello, Hideo Watanabe, Takashi Sato. Enhancer signature profiling identifies novel enhancer clusters for transcription factors in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2017-3363