Abstract
We investigated the role of lamin B2 in non-small cell lung cancer (NSCLC). We detected higher lamin B2 expression in 20 NSCLC tumor tissues obtained from The Cancer Genome Atlas than in adjacent normal lung tissues. LMNB2-RNAi knockdown in A549 and H1299 NSCLC cells inhibited colony formation, cell proliferation and G1-S cell cycle progression while increasing apoptosis. LMNB2 overexpression had the opposite effects. Tumor xenograft experiments showed diminished tumor growth with LMNB2 knockdown H1299 cells than with controls. Yeast two-hybrid studies revealed minichromosome maintenance complex component 7 (MCM7) to be a binding partner of lamin B2, which was confirmed by co-immunoprecipitation and co-localization studies. Lamin B2 binding enhanced DNA binding and helicase activities of MCM7. Deletion analysis with MCM7-N, MCM7-M or MCM7-C mutant proteins showed that lamin B2 binds to the C-terminus of MCM7, and competes with the binding of the tumor suppressor retinoblastoma (RB) protein. Immunohistochemical analysis of 150 NSCLC patient samples revealed that both lamin B2 and MCM7 levels positively correlated with histological grade and tumor TNM stage. Moreover, high lamin B2 and MCM7 levels correlated with shorter overall survival of NSCLC patients. In sum, these results show that lamin B2 interaction with MCM7 promotes NSCLC progression.
Highlights
Lamins are intermediate filament proteins that form a scaffold known as the nuclear lamina [1]
We demonstrated that lamin B2 regulates human non-small cell lung cancer (NSCLC) progression by binding to maintenance complex component 7 (MCM7) C-terminus and enhancing its chromatin binding and helcase activities
Lamin B2 interacts with the MCM7 C-terminus, which contains the helicase catalytic domain, whereas the N-terminal region participates in DNA binding [43,44,45]
Summary
Lamins are intermediate filament proteins that form a scaffold known as the nuclear lamina [1]. They are involved in tissue homeostasis and elicit large-scale or fine chromatin conformational changes, accelerate the DNA damage response, and affect transcription factor shuttling [2]. Lamins orchestrate the organization of the genome, which is essential for normal gene transcription and silencing, DNA replication and repair, positioning of nuclear pore complexes, chromatin remodeling, and nuclear envelope breakdown and reassembly during mitosis [3, 4, 5]. Lamin mutations are associated with increased DNA damage [8]. Laminopathies are a heterogenous group of diseases due to lamin mutations and/or defects in their expression or post-translational processing [9, 10]
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