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J Exp Med. 2019 Apr 23. pii: jem.20181394. doi: 10.1084/jem.20181394. [Epub ahead of print]

Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET.

Author information

1
Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research, Bad Nauheim, Germany.
2
Anatomy and Developmental Biology, Centre for Biomedicine and Medical Technology Mannheim (CBTM) and European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3
Microvascular Biology and Pathobiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
4
Institute of Neuropathology, Justus Liebig University, Giessen, Germany.
5
Institute of Pathology and Cytology, Überregionale Gemeinschaftspraxis für Pathologie (ÜGP), Wetzlar, Germany.
6
Department of Internal Medicine, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany.
7
Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research, Bad Nauheim, Germany gergana.dobreva@medma.uni-heidelberg.de.
8
Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany.

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.

PMID:
31015297
DOI:
10.1084/jem.20181394

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