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AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition.

ABSTRACT: Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition. Here, we report that nuclear deformation induced by TGFβ is concomitant with increased phosphorylation of lamin A at Ser390, defective nuclear lamina and genome instability. AKT2 and Smad3 serve as the downstream effectors for TGFβ to induce nuclear deformation. AKT2 directly phosphorylates lamin A at Ser390, whereas Smad3 is required for AKT2 activation upon TGFβ stimulation. Expression of the lamin A mutant with a substitution of Ser390 to Ala or suppression of AKT2 or Smad3 prevents nuclear deformation and genome instability induced by TGFβ. These findings reveal a molecular mechanism for TGFβ-induced nuclear deformation and establish a role of nuclear deformation in genome instability during epithelial-mesenchymal transition.

SUBMITTER: Fan JR

PROVIDER: S-EPMC10291577 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition.

Fan Jia-Rong JR Chang Sung-Nian SN Chu Ching-Tung CT Chen Hong-Chen HC

iScience 20230529 6

Nuclear deformation has been observed in some cancer cells for decades, but its underlying mechanism and biological significance remain elusive. To address these questions, we employed human lung cancer A549 cell line as a model in context with transforming growth factor β (TGFβ)-induced epithelial-mesenchymal transition. Here, we report that nuclear deformation induced by TGFβ is concomitant with increased phosphorylation of lamin A at Ser390, defective nuclear lamina and genome instability. AK ...[more]

PMID: 37378334

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Project description:Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and wound healing. Accordingly, CFTR has been proposed to function as a tumour suppressor in a wide range of cancers. Along these lines, CF was recently suggested to be associated with epithelial-mesenchymal transition (EMT), a latent developmental process, which can be re-activated in fibrosis and cancer. However, it is unknown whether EMT is indeed active in CF and if EMT is triggered by dysfunctional CFTR itself or a consequence of secondary complications of CF. In this study, we investigated the occurrence of EMT in airways native tissue, primary cells and cell lines expressing mutant CFTR through the expression of epithelial and mesenchymal markers as well as EMT-associated transcription factors. Transepithelial electrical resistance, proliferation and regeneration rates, and cell resistance to TGF-β1induced EMT were also measured. CF tissues/cells expressing mutant CFTR displayed several signs of active EMT, namely: destructured epithelial proteins, defective cell junctions, increased levels of mesenchymal markers and EMT-associated transcription factors, hyper-proliferation and impaired wound healing. Importantly, we found evidence that the mutant CFTR triggered EMT was mediated by EMT-associated transcription factor TWIST1. Further, our data show that CF cells are over-sensitive to EMT but the CF EMT phenotype can be reversed by CFTR modulator drugs. Altogether, these results identify for the first time that EMT is intrinsically triggered by the absence of functional CFTR through a TWIST1 dependent mechanism and indicate that CFTR plays a direct role in EMT protection. This mechanistic link is a plausible explanation for the high incidence of fibrosis and cancer in CF, as well as for the role of CFTR as tumour suppressor protein.

Dataset Information

AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition.

Publications

AKT2-mediated nuclear deformation leads to genome instability during epithelial-mesenchymal transition.

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