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Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET
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 we...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547854/ https://www.ncbi.nlm.nih.gov/pubmed/31015297 http://dx.doi.org/10.1084/jem.20181394 |
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author | Jia, Yanhan Vong, Joaquim Si-Long Asafova, Alina Garvalov, Boyan K. Caputo, Luca Cordero, Julio Singh, Anshu Boettger, Thomas Günther, Stefan Fink, Ludger Acker, Till Barreto, Guillermo Seeger, Werner Braun, Thomas Savai, Rajkumar Dobreva, Gergana |
author_facet | Jia, Yanhan Vong, Joaquim Si-Long Asafova, Alina Garvalov, Boyan K. Caputo, Luca Cordero, Julio Singh, Anshu Boettger, Thomas Günther, Stefan Fink, Ludger Acker, Till Barreto, Guillermo Seeger, Werner Braun, Thomas Savai, Rajkumar Dobreva, Gergana |
author_sort | Jia, Yanhan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6547854 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-65478542019-06-10 Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET Jia, Yanhan Vong, Joaquim Si-Long Asafova, Alina Garvalov, Boyan K. Caputo, Luca Cordero, Julio Singh, Anshu Boettger, Thomas Günther, Stefan Fink, Ludger Acker, Till Barreto, Guillermo Seeger, Werner Braun, Thomas Savai, Rajkumar Dobreva, Gergana J Exp Med Research Articles 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. Rockefeller University Press 2019-06-03 2019-04-23 /pmc/articles/PMC6547854/ /pubmed/31015297 http://dx.doi.org/10.1084/jem.20181394 Text en © 2019 Jia et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Jia, Yanhan Vong, Joaquim Si-Long Asafova, Alina Garvalov, Boyan K. Caputo, Luca Cordero, Julio Singh, Anshu Boettger, Thomas Günther, Stefan Fink, Ludger Acker, Till Barreto, Guillermo Seeger, Werner Braun, Thomas Savai, Rajkumar Dobreva, Gergana Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET |
title | Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET |
title_full | Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET |
title_fullStr | Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET |
title_full_unstemmed | Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET |
title_short | Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET |
title_sort | lamin b1 loss promotes lung cancer development and metastasis by epigenetic derepression of ret |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547854/ https://www.ncbi.nlm.nih.gov/pubmed/31015297 http://dx.doi.org/10.1084/jem.20181394 |
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