Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6.,Oncogene

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Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6.
Oncogene ( IF 6.9 ) Pub Date : 2020-03-10 , DOI: 10.1038/s41388-020-1246-z
Anna Arnal-Estapé _{1,

2} , Wesley L Cai ₁ , Alexandra E Albert ₃ , Minghui Zhao ₁ , Laura E Stevens _{1,

4} , Francesc López-Giráldez ₅ , Kiran D Patel ₁ , Siddhartha Tyagi _{6,

7} , Earlene M Schmitt _{6,

7} , Thomas F Westbrook _{6,

7,

8} , Don X Nguyen _{1,

2,

9}

Affiliation

Lineage selective transcription factors (TFs) are important regulators of tumorigenesis, but their biological functions are often context dependent with undefined epigenetic mechanisms of action. In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 in lung adenocarcinoma (LUAD) progression. Impairing Gata6 in genetically engineered mouse models reduces the proliferation and increases the differentiation of Kras mutant LUAD tumors. These effects are influenced by the epithelial cell type that is targeted for transformation and genetic context of Kras-mediated tumor initiation. In LUAD cells derived from surfactant protein C expressing progenitors, we identify multiple genomic loci that are bound by GATA6. Moreover, suppression of Gata6 in these cells significantly alters chromatin accessibility, particularly at distal enhancer elements. Analogous to its paradoxical activity in lung development, GATA6 expression fluctuates during different stages of LUAD progression and can epigenetically control diverse transcriptional programs associated with bone morphogenetic protein signaling, alveolar specification, and tumor suppression. These findings reveal how GATA6 can modulate the chromatin landscape of lung cancer cells to control their proliferation and divergent lineage dependencies during tumor progression.

中文翻译：

肺癌的肿瘤进展和染色质景观受谱系因子 GATA6 的调节。

谱系选择性转录因子（TF）是肿瘤发生的重要调节因子，但其生物学功能通常依赖于未定义的表观遗传作用机制。在这项研究中，我们发现了内胚层和肺特异性 TF GATA6 在肺腺癌 (LUAD) 进展中的条件作用。在基因工程小鼠模型中损害 Gata6 可减少 Kras 突变 LUAD 肿瘤的增殖并增加其分化。这些效应受到针对转化的上皮细胞类型和 Kras 介导的肿瘤起始的遗传背景的影响。在源自表达表面活性蛋白 C 的祖细胞的 LUAD 细胞中，我们鉴定了与 GATA6 结合的多个基因组位点。此外，抑制这些细胞中的 Gata6 会显着改变染色质的可及性，特别是在远端增强元件处。类似于其在肺发育中的矛盾活动，GATA6 表达在 LUAD 进展的不同阶段波动，并且可以表观遗传地控制与骨形态发生蛋白信号传导、肺泡规范和肿瘤抑制相关的多种转录程序。这些发现揭示了 GATA6 如何调节肺癌细胞的染色质景观，以控制肿瘤进展过程中的增殖和不同的谱系依赖性。

更新日期：2020-03-10

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