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Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells

Authors: Le-le Zhang1, Jun Lu1, Rui-qi Liu2, Min-juan Hu1, Yi-ming Zhao1, Sheng Tan3, Shu-yuan Wang1, Bo Zhang1, Wei Nie1, Yu Dong1, Hua Zhong1, Wei Zhang1, Xiao-dong Zhao3, Bao-hui Han1
1 Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
2 School of Biomedical Engineering, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
3 Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Correspondence to: Wei Zhang: zhwei2002@hotmail.com, Xiao-dong Zhao: xiaodongzhao@sjtu.edu.cn, Bao-hui Han: 18930858216@163.com,
DOI: 10.1038/s41401-020-0421-7
Received: 20 January 2020
Accepted: 15 April 2020
Advance online: 15 May 2020

Abstract

Anlotinib, a multitarget tyrosine kinase inhibitor, is effective as a third-line treatment against non-small cell lung cancer (NSCLC). However, acquired resistance occurs during its administration. To understand the molecular mechanisms of anlotinib resistance, we characterized chromatin accessibility in both the parental and anlotinib-resistant lung cancer cell line NCI-H1975 through ATAC-seq. Compared with the parental cells, we identified 2666 genomic regions with greater accessibility in anlotinib-resistant cells, in which angiogenesis-related processes and the motifs of 21 transcription factors were enriched. Among these transcription factors, TFAP2A was upregulated. TFAP2A knockdown robustly diminished tumor-induced angiogenesis and partially rescued the anti-angiogenic activity of anlotinib. Furthermore, transcriptome analysis indicated that 2280 genes were downregulated in anlotinib-resistant cells with TFAP2A knocked down, among which the PDGFR, TGF-β, and VEGFR signaling pathways were enriched. Meanwhile, we demonstrated that TFAP2A binds to accessible sites within BMP4 and HSPG2. Collectively, this study suggests that TFAP2A accelerates anlotinib resistance by promoting tumor-induced angiogenesis.
Keywords: anlotinib; acquired resistance; ATAC-seq; non-small cell lung cancer; TFAP2A

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