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

Yanhan Jia,Joaquim Si-Long Vong,Thomas Boettger,Ludger Fink,Gergana Dobreva,Rajkumar Savai,Luca Caputo,Werner Seeger,Stefan Günther,Anshu Singh,Thomas Braun,Boyan K Garvalov,Till Acker,Guillermo Barreto,Alina Asafova,Julio Cordero

doi:10.1084/jem.20181394

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.

Highlights

Lung cancer is the leading cause of cancer-related death et al, 2012; Burke and Stewart, 2013)
We found that derepression of the rearranged during transfection (RET) protooncogene and activation of the RET/p38 signaling axis mediates the malignant phenotype upon lamin B1 loss
Lamin B1 levels are significantly reduced in tumor cells of lung cancer patients but are high in immune cells, which have been shown to exhibit stage-dependent accumulation in human lung tumors (Banat et al, 2015) decrease of lamin B1 levels in lung cancer compared with nonmalignant lung cells/tissues was confirmed by Western blot analysis of mouse lung epithelial (MLE12) cells and normal human bronchial epithelium B2B (BEAS-2B) cells, compared with the highly aggressive, metastatic mouse Lewis lung carcinoma (LLC1) cells, as well as H69 human SCLC cells (Fig. S1 E)

Summary

Introduction

Lung cancer is the leading cause of cancer-related death et al, 2012; Burke and Stewart, 2013). NSCLC, which accounts pathway (Stewart and Burke, 1987), suggesting distinct molecfor ∼80% of all cases, is subdivided into adenocarcinoma, squa- ular functions of A- and B-type lamins in different cell types. Cluding characteristic changes in nuclear shape and size, the high-resolution confocal microscopy demonstrated that the number of nucleoli and nuclear bodies, chromatin appearance, different type of lamins form distinct meshworks, which show and a “polymorphic” nuclear envelope with abnormal nuclear low colocalization, further suggesting distinct functions. The nu- B1 binding identified large lamina-associated domains (LADs), clear envelope, which is an important determinant of nuclear consisting of megabase-sized, relatively gene-poor, and represstructure, shape, and genome integrity, is composed of nuclear sive chromatin domains, that dynamically associate with the membranes, nuclear lamina, and nuclear pore complexes (Bukata nuclear lamina (Guelen et al, 2008; Reddy et al, 2008; Pericet al., 2013; Van Bortle and Corces, 2013).

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