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.
- Jia, Y.
- Vong, J. S.
- Asafova, A.
- Garvalov, B. K.
- Caputo, L.
- Cordero, J.
- Singh, A.
- Boettger, T.
- Gunther, S.
- Fink, L.
- Acker, T.
- Barreto, G.
- Seeger, W.
- Braun, T.
- Savai, R.
- Dobreva, G.
