Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET [ChIP-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: ChIP-seq for H3K27me3 of control (n=2; H3K27me3_Lmnb1_ctrl_MLE12_ChIP_seq_rep1 and H3K27me3_Lmnb1_ctrl_MLE12_ChIP_seq_rep2) and lamin B1 knockdown (n=2; H3K27me3_Lmnb1_KD_MLE12_ChIP_seq_rep1 and H3K27me3_Lmnb1_KD_MLE12_ChIP_seq_rep2) MLE12 cells along with respective input samples.