Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET.
Fiche publication
Date publication
juin 2019
Journal
The Journal of experimental medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BARRETO Guillermo
Tous les auteurs :
Jia Y, Vong JS, Asafova A, Garvalov BK, Caputo L, Cordero J, Singh A, Boettger T, Günther S, Fink L, Acker T, Barreto G, Seeger W, Braun T, Savai R, Dobreva G
Lien Pubmed
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.
Mots clés
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 Proteins c-ret, metabolism, Signal Transduction, Up-Regulation, genetics
Référence
J Exp Med. 2019 06 3;216(6):1377-1395