Journal article

Publication year: 2019

Pages: 1377-1395

Journal: Journal of Experimental Medicine

Volume number: 216

Issue number: 6

ISSN: 0022-1007

eISSN: 1540-9538

Open access status: Hybrid

DOI Link: https://doi.org/10.1084/jem.20181394

Publisher: Rockefeller University Press

Abstract: 
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.

Harvard Citation style: Jia, Y., Vong, J., Asafova, A., Garvalov, B., Caputo, L., Cordero, J., et al. (2019) Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET, Journal of Experimental Medicine, 216(6), pp. 1377-1395. https://doi.org/10.1084/jem.20181394

APA Citation style: Jia, Y., Vong, J., Asafova, A., Garvalov, B., Caputo, L., Cordero, J., Singh, A., Boettger, T., Guenther, S., Fink, L., Acker, T., Barreto, G., Seeger, W., Braun, T., Savai, R., & Dobreva, G. (2019). Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET. Journal of Experimental Medicine. 216(6), 1377-1395. https://doi.org/10.1084/jem.20181394