Abstract
Abstract Lung cancer is the leading cause of cancer death among both men and women in United States. ELF3, a transcription factor, overexpresses in human and mouse lung cancer and plays an oncogenic role in lung cancer cells1,2. Understanding the regulatory mechanisms for ELF3 may help to develop related target therapies. Ablation of Smad4 and Pten in mice results in an increase of Elf3 expression and the development of adeno-squamous carcinoma1. Results from in vivo ChIP-Seq analysis demonstrate SMAD4 occupancy near the Elf3 promoter in the pulmonary epithelium1. Therefore, we hypothesize that this SMAD4 occupancy is required to repress Elf3 expression and subsequently suppresses lung cancer progression. To test this hypothesis, we deleted this SMAD4 binding region in vivo and characterized the phenotypic consequences. CRISPR/Cas9 was used to ablate the SMAD4 ChIP-Seq binding peak on Elf3 promoter region in mice. This resulted in mice with 12 and 17 nucleotide deletions in the Elf3 promoter region. ChIP-qPCR analysis showed that SMAD4 binding was decreased while H3K27ac bindings were increased in the Elf3 promoter region. The reduction in SMAD4 binding and the epigenetic changes in the Elf3 promoter region resulted in an increased expression of ELF3 in these lungs of these mice. Histological analysis of these mouse lungs showed the presence of pulmonary hyperplasia and the development of lung tumors. In order to identify potential interacting factors with SMAD4 in the Elf3 promoter, motif analysis of the deleted SMAD4 binding peak identified GATA2, ETS1 and OXT2 as potential interacting factors. In summary, small disruption of Elf3 promoter region bound by SMAD4 leads to the increase of ELF3 expression with the enhanced binding of H3K27ac and the decrease of SMAD4 binding and promotes lung hyperplasia and lung cancer development. SMAD4 may interact with GATA2, ETS2 and OXT2 in the regulation of Elf3expression. Key references 1. Liu, J. et al. ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis. Cell Rep, doi:10.1016/j.celrep.2015.02.014 (2015). 2. Wang, H. et al. Overexpression of ELF3 facilitates cell growth and metastasis through PI3K/Akt and ERK signaling pathways in non-small cell lung cancer. Int J Biochem Cell Biol 94, 98-106, doi:10.1016/j.biocel.2017.12.002 (2018). Note: This abstract was not presented at the meeting. Citation Format: Jian Liu, Tianyuan Wang, San-pin Wu, Jian-liang Li, Francesco J. Demayo. Ablation of SMAD4 repression on Elf3 promotes the progression of lung cancer in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5212.
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