Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells.
Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells.
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染色质可及性分析表明 TFAP2A 促进肺癌细胞安罗替尼获得性耐药中的血管生成
DOI：
10.1038/s41401-020-0421-7
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发表时间：
2020-10
影响因子：
8.2
通讯作者：
Han BH
中科院分区：
文献类型：
--
作者：
Zhang LL;Lu J;Liu RQ;Hu MJ;Zhao YM;Tan S;Wang SY;Zhang B;Nie W;Dong Y;Zhong H;Zhang W;Zhao XD;Han BH
安洛替尼是一种多靶点酪氨酸激酶抑制剂，作为非小细胞肺癌（NSCLC）的三线治疗有效。然而，在给药期间会发生获得性耐药性。为了理解安洛替尼耐药的分子机制，我们通过ATAC-seq表征了亲本和安洛替尼耐药肺癌细胞系NCI-H1975中的染色质可及性。与亲本细胞相比，我们确定了2666个基因组区域，在安洛替尼耐药细胞中具有更大的可及性，其中血管生成相关过程和21个转录因子的基序富集。在这些转录因子中，TFAP 2A被上调，TFAP 2A的敲低可显著降低肿瘤诱导的血管生成，并部分挽救了安洛替尼的抗血管生成活性。转录组分析显示，下调TFAP 2A基因后，有2280个基因表达下调，其中PDGFR、TGF-β和VEGFR信号通路表达丰富。同时，我们证明TFAP 2A与BMP 4和HSPG 2的可及位点结合。总的来说，这项研究表明，TFAP 2A通过促进肿瘤诱导的血管生成加速了安洛替尼的耐药性。
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,TFAP2Awas upregulated.TFAP2Aknockdown 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 withTFAP2Aknocked down, among which the PDGFR, TGF-β, and VEGFR signaling pathways were enriched. Meanwhile, we demonstrated thatTFAP2Abinds to accessible sites withinBMP4andHSPG2. Collectively, this study suggests thatTFAP2Aaccelerates anlotinib resistance by promoting tumor-induced angiogenesis.
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