FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma.
FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma.
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FoxA1/2 依赖性表观基因组重编程驱动肺腺癌谱系转换。
DOI：
10.1101/2023.10.30.564775
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Snyder,EricL
中科院分区：
文献类型：
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作者：
Gillis,Katherine;Orellana,WalterA;Wilson,Emily;Parnell,TimothyJ;Fort,Gabriela;Dadzie,HeadtloveEssel;Zhang,Xiaoyang;Snyder,EricL
癌细胞经历身份改变的能力（即，谱系可塑性）在肿瘤进展和对治疗的反应中起关键作用。在KRAS驱动的肺腺癌（LUAD）中，肺谱系特异性NKX 2 -1的缺失增强了肿瘤进展，并导致FoxA 1/2依赖性肺至胃谱系转换。然而，FoxA 1/2在肺中激活潜在胃身份的机制在很大程度上仍然未知。在这里，我们发现FoxA 1/2通过促进10 - 11易位（泰特）2/3募集、DNA去甲基化、组蛋白3赖氨酸27乙酰化（H3 K27 ac）沉积和三维（3D）染色质相互作用，在小鼠模型中NKX 2 -1丢失后重新编程胃特异性基因的表观遗传景观。FoxA 1/2介导的DNA甲基化变化在人内胚层发育和人肺和胰腺肿瘤进展中高度保守。此外，致癌信号是FoxA 1/2依赖性表观遗传重编程的特定元件所必需的。这项工作证明了FoxA 1/2在重新连接NKX 2 -1阴性LUAD的DNA甲基化和3D染色质景观以驱动癌细胞谱系转换中的作用。
The ability of cancer cells to undergo identity changes (i.e., lineage plasticity) plays a key role in tumor progression and response to therapy. Loss of the pulmonary lineage specifier NKX2-1 in KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and causes a FoxA1/2-dependent pulmonary-to-gastric lineage switch. However, the mechanisms by which FoxA1/2 activate a latent gastric identity in the lung remain largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of gastric-specific genes after NKX2-1 loss in mouse models by facilitating ten-eleven translocation (TET)2/3 recruitment, DNA demethylation, histone 3 lysine 27 acetylation (H3K27ac) deposition, and three-dimensional (3D) chromatin interactions. FoxA1/2-mediated DNA methylation changes are highly conserved in human endodermal development and in progression of human lung and pancreatic neoplasia. Furthermore, oncogenic signaling is required for specific elements of FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the DNA methylation and 3D chromatin landscape of NKX2-1-negative LUAD to drive cancer cell lineage switching.