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Janetzko, J.; Oeck, S.; Schramm, A. Role of Lamins in Lung Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/52516 (accessed on 28 July 2024).
Janetzko J, Oeck S, Schramm A. Role of Lamins in Lung Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/52516. Accessed July 28, 2024.
Janetzko, Janina, Sebastian Oeck, Alexander Schramm. "Role of Lamins in Lung Cancer" Encyclopedia, https://encyclopedia.pub/entry/52516 (accessed July 28, 2024).
Janetzko, J., Oeck, S., & Schramm, A. (2023, December 08). Role of Lamins in Lung Cancer. In Encyclopedia. https://encyclopedia.pub/entry/52516
Janetzko, Janina, et al. "Role of Lamins in Lung Cancer." Encyclopedia. Web. 08 December, 2023.
Role of Lamins in Lung Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15235501

Lamins are type V intermediate filament proteins that are best known for their scaffolding function in the nucleus of eukaryotic cells. Lamins are encoded by the LMNA, LMNB1, and LMNB2 genes, giving rise to seven known lamin variants due to alternative splicing. In physiological settings, lamins play important roles in maintaining the integrity of the nuclear envelope, regulating DNA replication and transcription, and organizing the chromatin structure. Germline alterations in the lamin-encoding genes give rise to a multitude of disorders such as disturbed fat and skeletal homeostasis and syndromes that are summarized as laminopathies. These syndromes include cardiomyopathies, muscular dystrophies, and premature-aging-like syndromes such as the Hutchinson–Gilford progeria syndrome (HGPS). HGPS is caused by abnormal splicing of prelamin A, resulting in a shortened isoform that is referred to as lamin AΔ50, AΔ150, or progerin. Lamin B-related diseases include lipodystrophy and brain disorders such as adult-onset autosomal dominant leukodystrophy (ADLD). While laminopathies are rare diseases, the underlying mutations provide insights into the function and organization of lamin proteins. 

lamins lung cancer lamin composition DNA repair kinases

1. Introduction

Lung cancer is divided into two subtypes, namely the more frequently occurring non-small-cell lung cancers (NSCLC) and small-cell lung cancers (SCLC), which account for roughly 85% and 15% of all lung cancers, respectively. Depending on the subtype, varying levels of lamin A/C were detected in lung tumor cells. SCLC expresses LMNA at lower levels compared to NSCLC tumor tissues [1][2]. In pre-clinical models, conflicting results have been reported by Stefanello et al. [3], who found decreased lamin A/C levels in the lung adenocarcinoma (LUAD) cell line A549, while Rubporn et al. [4] reported LMNA overexpression in the same cell line. Furthermore, Hu et al. [5] reported that lamin A/C contributes to acquired resistance to erlotinib in EGFR-mutant NSCLC. They analyzed cytoskeletal changes and found increased nuclear deformation upon the modulation of LMNA expression. Based on these findings, they suggested that reduced LMNA expression contributes to higher nuclear plasticity. As for lamin A/C, different effects of lamin B1 on lung cancer biology were reported: Jia et al. [2] identified decreased lamin B1 expression as a lung cancer-promoting factor, whereas two reports by Li et al. [6] and Li et al. [7] suggested that lamin B1 overexpression correlated with advanced-stage NSCLC. Interestingly, lamin B2 expression levels were unanimously correlated with a higher clinical stage [8][9][10]; however, the mechanism underlying lamin B2 regulation still needs clarification. Taken together, dysregulation of the different lamin proteins is observed in lung cancer, but the impact derived thereof remains controversial. However, three eminent functions of lamins have been identified that seem to depend on the expression of the different lamin subtypes and that can be hijacked in lung cancer cells: 1. cell cycle regulation induced by receptor tyrosine kinase or protein kinase signaling that affects lamin polymerization by phosphorylation; 2. chromatin organization and compactness that can impact transcriptional activity; and 3. cellular stiffness and mobility that can be molecularly linked to lamin interaction with proteins regulating EMT. Beyond these central processes, lamins might also contribute to DNA damage response and repair pathways ([11], also reviewed in [12]).

2. Role of Lamin Dysregulation in DNA Damage Response, Cell Cycle Transition, and DNA Repair

The facts that nuclear integrity mediated by lamins controls cell fate and that rupture of the nuclear lamina is a catastrophic event causing programmed cell death are well acknowledged. However, in genomically unstable cancer cells, controlling functions of lamins can be overruled and hijacked. A prime example is the formation of lamin B1-containing micronuclei in lung cancer cells that form around missegregated chromosomes during mitotic exit, which in turn can contribute to genomic instability and even potentiate it [11]. Still, this structural function of lamins is only one side of the coin, as lamins can also interact with proteins that directly control cell cycle and proliferation.
Rubporn et al. [4] found that lamin A/C and several co-regulated proteins including KAP1 (TIF1β, TRIM28) were overexpressed in the A549 lung cancer cell line compared to MRC-5 normal lung fibroblast cells. Interestingly, Neumann-Staubitz et al. [13] identified KAP1 as an interactor of the Ig-domain of lamin C using genetically encoded crosslinkers. KAP1 is involved in cell survival after DNA damage and its phosphorylation by ATM, ATR, and DNA-PK recruits KAP1 to DNA strand breaks [14]. Furthermore, KAP1 is part of the transcription intermediary factor 1 (TIF1) sub-group, whose members possess a bromodomain (Bromo) and a plant homeodomain (PHD), which are common reader domains for the epigenetic code of histone post-translational modifications [15][16]. KAP1 was found to directly interact with MDM2, leading to the recruitment of the p53-HDAC1 complex that results in p53 inhibition and impaired apoptosis [17][18]. Consequently, the interaction of KAP1 with lamin C and its upregulation indicates a function of lamin A/C in cell survival in A549 cells, which needs to be verified in additional model systems.
In addition to lamin A/C, B-type lamins were reported to be deregulated in lung cancer. Immunohistology and biochemical analyses suggested that lamin B2 is upregulated in NSCLC and promotes aggressiveness by inducing or interacting with KLF16, MCM7, and G9a [8][9][10]. Here, expression of G9a depended on both lamin B2 and cyclin D1 expression, contributing to enhanced cell migration and cell cycle progression. Ma et al. [9] reported cell proliferation after overexpression of LMNB2 and impaired G1/S cell cycle progression upon lamin B2 knockdown with concomitantly decreased levels of cyclin D1 and cyclin E1. Interestingly, cyclin B1 expression and G2/M phase transition seemed to be unaffected by lamin B2 levels, suggesting that lamin B2 specifically targets G1/S transition. However, overexpression of another lamin B2 interaction partner, KLF16, in H1299 and H1975 LUAD cell lines resulted in lamin B2 upregulation accompanied by enhanced proliferation and migration. Here, the fraction of cells in the G0/G1 phase decreased while G2/M cells were increased. Taken together, these results indicate that lamin B2 expression levels can impact cell cycle progression via different mechanisms. Furthermore, changes in lamin expression levels do not only influence nuclear stability and cell cycle progression, they also affect the organization of chromatin structure and thereby transcriptional regulation.

3. Lamin Dysregulation and Chromatin Organization in Lung Cancer

The interaction between chromatin and the nuclear lamina determines, at least in part, chromatin structure and accessibility [19]. At present, it is not known how the specificity of these interactions is regulated and how this physiological role of creating permissive or restrictive environments for gene transcription is hijacked in cancer cells. Interestingly, inactivation of FAK was reported to induce cellular senescence and p53 upregulation [20]. Recently, Chuang et al. [21] further investigated the mechanism of FAK-diminished senescence involving the enhancer of zeste homolog 2 (EZH2), which is a histone methyltransferase within the PRC2-repressor complex regulating H3K27 methylation and gene silencing [22][23]. Inhibition of EZH2 was previously reported to be involved in the onset of senescence in different cancer types such as triple-negative breast cancer or pancreatic cancer [24][25]. Furthermore, it was shown that FAK inhibition leads to senescence in lung cancer involving the downregulation of EZH2, suggesting a functional correlation of EZH2 and FAK in non-small cell lung cancer [21]. Interestingly, lamin B1 was reported to specifically interfere with the function of EZH2 [2]. By depleting lamin B1, Jia et al. [2] showed that chromatin-bound EZH2 was reduced concomitant with a decrease in H3K27me3. They suggested that lamin B1 is important for H3K27me3-mediated chromatin accessibility and transcriptional regulation [2]. These results and the aforementioned in vitro reports underscore that lamin A/C and lamin B1 could both contribute to the dysregulation of cellular senescence and epigenetic modifiers involved in cell division in lung cancer.

4. Impact of Lamin Dysregulation on Cellular Mobility, Plasticity, and EMT in Lung Cancer Cells and Lung Metastases

The plasticity and dynamic regulation of lamin proteins in lung cancer cells are highly debated and poorly understood. Hu et al. [5] investigated the consequences of downregulating LMNA in lung cancer cells on EMT by quantifying the ratio of E-cadherin and vimentin. In cells with reduced LMNA levels, E-cadherin was downregulated and vimentin was upregulated, indicating EMT accompanied by enhanced migration and invasion [5]. In a corresponding approach, Jia et al. [2] showed that depletion of lamin B1 in normal mouse lung epithelial cells induced the downregulation of E-cadherin and upregulation of the mesenchymal markers fibronectin, vimentin, and N-cadherin. Moreover, loss of lamin B1 led to upregulation of the proto-oncogene RET and its coreceptor GFRA1 together with upregulation of the MAP kinase p38. RET is a member of the receptor tyrosine kinase family and its activation stimulates several pathways, including the MAPK and PI3K/AKT signaling pathways (reviewed in [26]), which are involved in EMT (reviewed in [27]). Therefore, loss of lamin B1 could contribute to EMT via the activation of RET and its downstream function in the MAPK and PI3K/AKT pathways. On the contrary, Li et al. [6] reported that lamin B1 overexpression in LUAD was sufficient to activate the AKT/pAKT pathway. Depletion of lamin B1 slowed the tumor growth of A549 cells concomitant with decreased phosphorylation of AKT. They suggested that lamin B1 regulates cell proliferation in an AKT-dependent manner and that lamin B1 may function as an oncogene in LUAD. Interestingly, Pascual-Reguant et al. [28] showed that lamin B1 expression is essential for the acquisition of mesenchymal traits during EMT in the epithelial-like mouse cell line NMuMG. However, the role of lamin B1 in the context of EMT needs to be consolidated, as lamin B1 orchestrates signals from different pathways including AKT signaling, which could induce cell type-specific responses.

References

  1. Wang, J.; Kondo, T.; Nakazawa, T.; Oishi, N.; Mochizuki, K.; Katoh, R. Constitutional abnormality of nuclear membrane proteins in small cell lung carcinoma. Virchows Arch. 2019, 475, 407–414.
  2. Jia, Y.; Vong, J.S.-L.; Asafova, A.; Garvalov, B.K.; Caputo, L.; Cordero, J.; Singh, A.; Boettger, T.; Günther, S.; Fink, L.; et al. Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET. J. Exp. Med. 2019, 216, 1377–1395.
  3. Stefanello, S.T.; Luchtefeld, I.; Liashkovich, I.; Pethö, Z.; Azzam, I.; Bulk, E.; Rosso, G.; Döhlinger, L.; Hesse, B.; Oeckinghaus, A.; et al. Impact of the Nuclear Envelope on Malignant Transformation, Motility, and Survival of Lung Cancer Cells. Adv. Sci. 2021, 8, e2102757.
  4. Rubporn, A.; Srisomsap, C.; Subhasitanont, P.; Chokchaichamnankit, D.; Chiablaem, K.; Svasti, J.; Sangvanich, P. Comparative proteomic analysis of lung cancer cell line and lung fibroblast cell line. Cancer Genom. Proteom. 2009, 6, 229–237.
  5. Hu, C.; Zhou, A.; Hu, X.; Xiang, Y.; Huang, M.; Huang, J.; Yang, D.; Tang, Y. LMNA Reduced Acquired Resistance to Erlotinib in NSCLC by Reversing the Epithelial-Mesenchymal Transition via the FGFR/MAPK/c-fos Signaling Pathway. Int. J. Mol. Sci. 2022, 23, 13237.
  6. Li, W.; Li, X.; Li, X.; Li, M.; Yang, P.; Wang, X.; Li, L.; Yang, B. Lamin B1 Overexpresses in Lung Adenocarcinoma and Promotes Proliferation in Lung Cancer Cells via AKT Pathway. Onco. Targets. Ther. 2020, 13, 3129–3139.
  7. Li, J.; Sun, Z.; Cui, Y.; Qin, L.; Wu, F.; Li, Y.; Du, N.; Li, X. Knockdown of LMNB1 Inhibits the Proliferation of Lung Adenocarcinoma Cells by Inducing DNA Damage and Cell Senescence. Front. Oncol. 2022, 12, 913740.
  8. Jiao, X.; Gao, W.; Ren, H.; Wu, Y.; Li, T.; Li, S.; Yan, H. Kruppel like factor 16 promotes lung adenocarcinoma progression by upregulating lamin B2. Bioengineered 2022, 13, 9482–9494.
  9. Ma, Y.; Fei, L.; Zhang, M.; Zhang, W.; Liu, X.; Wang, C.; Luo, Y.; Zhang, H.; Han, Y. Lamin B2 binding to minichromosome maintenance complex component 7 promotes non-small cell lung carcinogenesis. Oncotarget 2017, 8, 104813–104830.
  10. Zhang, M.-Y.; Han, Y.-C.; Han, Q.; Liang, Y.; Luo, Y.; Wei, L.; Yan, T.; Yang, Y.; Liu, S.-L.; Wang, E.-H. Lamin B2 promotes the malignant phenotype of non-small cell lung cancer cells by upregulating dimethylation of histone 3 lysine 9. Exp. Cell Res. 2020, 393, 112090.
  11. Hatch, E.M.; Fischer, A.H.; Deerinck, T.J.; Hetzer, M.W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 2013, 154, 47–60.
  12. de Leeuw, R.; Gruenbaum, Y.; Medalia, O. Nuclear Lamins: Thin Filaments with Major Functions. Trends Cell Biol. 2018, 28, 34–45.
  13. Neumann-Staubitz, P.; Kitsberg, D.; Buxboim, A.; Neumann, H. A method to map the interaction network of the nuclear lamina with genetically encoded photo-crosslinkers in vivo. Front. Chem. 2022, 10, 905794.
  14. White, D.E.; Negorev, D.; Peng, H.; Ivanov, A.V.; Maul, G.G.; Rauscher, F.J. KAP1, a novel substrate for PIKK family members, colocalizes with numerous damage response factors at DNA lesions. Cancer Res. 2006, 66, 11594–11599.
  15. Sanchez, R.; Zhou, M.-M. The PHD finger: A versatile epigenome reader. Trends Biochem. Sci. 2011, 36, 364–372.
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  18. Wang, C.; Rauscher, F.J.; Cress, W.D.; Chen, J. Regulation of E2F1 function by the nuclear corepressor KAP1. J. Biol. Chem. 2007, 282, 29902–29909.
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  20. Chuang, H.-H.; Wang, P.-H.; Niu, S.-W.; Zhen, Y.-Y.; Huang, M.-S.; Hsiao, M.; Yang, C.-J. Inhibition of FAK Signaling Elicits Lamin A/C-Associated Nuclear Deformity and Cellular Senescence. Front. Oncol. 2019, 9, 22.
  21. Chuang, H.-H.; Huang, M.-S.; Zhen, Y.-Y.; Chuang, C.-H.; Lee, Y.-R.; Hsiao, M.; Yang, C.-J. FAK Executes Anti-Senescence via Regulating EZH2 Signaling in Non-Small Cell Lung Cancer Cells. Biomedicines 2022, 10, 1937.
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  24. Yu, Y.; Qi, J.; Xiong, J.; Jiang, L.; Cui, D.; He, J.; Chen, P.; Li, L.; Wu, C.; Ma, T.; et al. Epigenetic Co-Deregulation of EZH2/TET1 is a Senescence-Countering, Actionable Vulnerability in Triple-Negative Breast Cancer. Theranostics 2019, 9, 761–777.
  25. Chibaya, L.; Murphy, K.C.; DeMarco, K.D.; Gopalan, S.; Liu, H.; Parikh, C.N.; Lopez-Diaz, Y.; Faulkner, M.; Li, J.; Morris, J.P.; et al. EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance. Nat. Cancer 2023, 4, 872–892.
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  27. Otsuki, Y.; Saya, H.; Arima, Y. Prospects for new lung cancer treatments that target EMT signaling. Dev. Dyn. 2018, 247, 462–472.
  28. Pascual-Reguant, L.; Blanco, E.; Galan, S.; Le Dily, F.; Cuartero, Y.; Serra-Bardenys, G.; Di Carlo, V.; Iturbide, A.; Cebrià-Costa, J.P.; Nonell, L.; et al. Lamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains. Nat. Commun. 2018, 9, 3420.
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Subjects: Oncology
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Janina Janetzko
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Alexander Schramm
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Update Date: 08 Dec 2023
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