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.
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Acknowledgements
This research was funded by the National Key Research and Development Program of China (number 2018YFC1003501), the System Biomedicine Innovation Center Program from Shanghai Jiao Tong University (number 15ZH4009), the Key Translational Medicine Program from Shanghai Jiao Tong University School of Medicine (number 15ZH1008), and the National Natural Science Foundation of China (number 81874037).
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LLZ, JL, and RQL performed the experiment. LLZ wrote the paper. MJH, YMZ, ST, SYW, BZ, WN, YD, and HZ helped to analyzed the data. BHH, XDZ, and WZ designed the study and performed manuscript editing.
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Zhang, Ll., Lu, J., Liu, Rq. et al. Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells. Acta Pharmacol Sin 41, 1357–1365 (2020). https://doi.org/10.1038/s41401-020-0421-7
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DOI: https://doi.org/10.1038/s41401-020-0421-7
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