Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [ATAC-seq]

DICER1 canonically regulates micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinomas (LUADs). We discovered that KRAS/ERK pathway phosphorylates DICER1 causing its nuclear translocation; phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. Here, we show that phospho-DICER1 is expressed in invasive human LUADs and promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Strikingly, in mice, we observed that the AT2 tumor cells with phospho-DICER1 express endodermal (gastric) genes and display an open chromatin state such that there are sub-populations of tumors cells with alveolar-endodermal or only endodermal identity. Importantly, we also observed expression of gastric genes in human LUADs with phospho-DICER1. Mechanistically, we identify a chromatin-DICER1 nuclear complex comprised of Mediator complex subunit 12, CBX1, MACROH2A.1 and transcriptional regulators. Together, we propose that phosphorylated-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression. Chromatin accessibility across the genome of KrasLA1/+;Dicer1S2D/+ lung tumors was determined by ATAC sequencing.

DICER1在肺腺癌（lung adenocarcinomas, LUADs）中经典调控微小RNA（microRNA, miRNA）所介导的上皮间质转化（epithelial-to-mesenchymal transition, EMT）过程。本研究团队发现，KRAS/ERK信号通路可通过磷酸化修饰DICER1，促使其发生核转位；磷酸化模拟型Dicer1（phosphomimetic Dicer1）可促进小鼠体内的肿瘤发生。目前，磷酸化DICER1调控肿瘤进展的具体分子机制仍未明确。本研究证实，磷酸化DICER1在侵袭性人类肺腺癌中表达，并可在携带致癌性Kras的小鼠中促进肿瘤晚期进展，且该过程不依赖于微小RNA及上皮间质转化。值得注意的是，在小鼠模型中，携带磷酸化DICER1的肺泡II型细胞（alveolar type II cells, AT2）可表达内胚层（胃源性）基因，并呈现染色质开放状态，因此存在两类肿瘤细胞亚群：一类兼具肺泡-内胚层特性，另一类仅具备内胚层特性。重要的是，我们在携带磷酸化DICER1的人类肺腺癌样本中同样观察到了胃源性基因的表达。机制层面，本研究鉴定出一种由中介体复合物亚基12（Mediator complex subunit 12）、CBX1蛋白、MacroH2A.1组蛋白变体（MACROH2A.1）及转录调控因子组成的染色质-DICER1核复合物。综上，我们提出假说：磷酸化的核定位DICER1可介导肺泡II型肿瘤细胞发生谱系重编程，进而促进肺癌进展。本研究通过ATAC测序（ATAC-sequencing）解析了KrasLA1/+;Dicer1S2D/+基因工程小鼠肺肿瘤的全基因组染色质可及性。