Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET.
Animals
Carcinogenesis
/ genetics
Cell Line, Tumor
Chromatin
/ metabolism
Enhancer of Zeste Homolog 2 Protein
/ metabolism
Epigenesis, Genetic
Epithelial Cells
/ metabolism
Epithelial-Mesenchymal Transition
/ genetics
Female
Gene Expression Regulation, Neoplastic
Haploinsufficiency
/ genetics
Humans
Lamin Type B
/ metabolism
Lung Neoplasms
/ genetics
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasm Grading
Neoplasm Metastasis
Phenotype
Polycomb Repressive Complex 2
/ metabolism
Proto-Oncogene Mas
Proto-Oncogene Proteins c-ret
/ metabolism
Signal Transduction
Up-Regulation
/ genetics
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
03 06 2019
03 06 2019
Historique:
received:
22
07
2018
revised:
13
02
2019
accepted:
20
03
2019
pubmed:
25
4
2019
medline:
15
4
2020
entrez:
25
4
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31015297
pii: jem.20181394
doi: 10.1084/jem.20181394
pmc: PMC6547854
doi:
Substances chimiques
Chromatin
0
Lamin Type B
0
MAS1 protein, human
0
Proto-Oncogene Mas
0
EZH1 protein, human
EC 2.1.1.43
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Polycomb Repressive Complex 2
EC 2.1.1.43
Proto-Oncogene Proteins c-ret
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1377-1395Informations de copyright
© 2019 Jia et al.
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