Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET [RNA-Seq]

Although abnormal nuclear structure is an important criterion for cancer diagnostics, remarkably little is known about its relationship to tumor development. Here we report that loss of lamin B1, a determinant of nuclear architecture, plays a key role in lung cancer. We found that lamin B1 levels were reduced in lung cancer patients. Lamin B1 silencing in lung epithelial cells promoted epithelial-mesenchymal transition, cell migration, tumor growth and metastasis. Mechanistically, we show that lamin B1 recruits the polycomb repressive complex 2 (PRC2) to alter the H3K27me3 landscape and repress genes involved in cell migration and signaling. In particular, epigenetic derepression of the RET proto-oncogene by loss of PRC2 recruitment, and activation of the RET/p38 signaling axis, play a crucial role in mediating the malignant phenotype upon lamin B1 disruption. Importantly, loss of a single lamin B1 allele induced spontaneous lung tumor formation and RET activation. Thus, lamin B1 acts as a tumor suppressor in lung cancer, linking aberrant nuclear structure and epigenetic patterning with malignancy. Overall design: RNA-seq analysis of control (n=2; Lmnb1_ctrl_MLE12_RNA_seq_rep1 and Lmnb1_ctrl_MLE12_RNA_seq_rep2) and lamin B1 knockdown (n=2; Lmnb1_KD_MLE12_RNA_seq_rep1 and Lmnb1_KD_MLE12_RNA_seq_rep2) MLE12 cells.

尽管细胞核结构异常是癌症诊断的重要判定标准，但目前对其与肿瘤发生发展的关联仍知之甚少。本研究证实，作为核架构决定因子的核纤层蛋白B1（lamin B1）缺失在肺癌进程中发挥关键作用。我们检测到肺癌患者体内的核纤层蛋白B1水平显著下调。在肺上皮细胞中沉默核纤层蛋白B1可促进上皮间质转化、细胞迁移、肿瘤生长与远处转移。机制层面，我们发现核纤层蛋白B1可招募多梳抑制复合体2（polycomb repressive complex 2，PRC2），以此改变H3K27me3修饰谱，并抑制参与细胞迁移与信号通路的基因表达。尤为关键的是，因无法正常招募PRC2导致的RET原癌基因表观去抑制，以及RET/p38信号轴的激活，在核纤层蛋白B1缺失引发的恶性表型中起到核心介导作用。值得注意的是，仅缺失单个核纤层蛋白B1等位基因即可诱发自发性肺肿瘤形成并激活RET信号通路。综上，核纤层蛋白B1可作为肺癌中的抑癌因子，将异常核结构与表观遗传模式紊乱和恶性表型直接关联起来。实验设计：对对照组（样本量n=2，包含Lmnb1_ctrl_MLE12_RNA_seq_rep1与Lmnb1_ctrl_MLE12_RNA_seq_rep2）及核纤层蛋白B1敲低组（样本量n=2，包含Lmnb1_KD_MLE12_RNA_seq_rep1与Lmnb1_KD_MLE12_RNA_seq_rep2）的MLE12细胞开展RNA测序分析。