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Published on: February 11, 2019
A Novel Emerin/Nesprin-3 Interaction Mediates Nuclear Size Changes Induced by Oncogenic KRAS in Pancreatic Cancer
Kayla C LaRue-Nolan1,2, Luis F Flores1, Renzo E Vera1
1Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Abstract:
Nuclear envelope (NE) proteins are essential for maintaining nuclear morphology, a central process controlling cellular phenotypes. While these proteins and structures are largely characterized in developmental biology, their function and associated abnormal nuclear morphology in disease, in particular cancer, remain elusive. We reported that throughout pancreatic transformation, oncogenic mutant KRAS (mKRAS) alters cancer cells nuclear size. Furthermore, we identified the NE protein Emerin as a mediator of these nuclear changes. Emerin's function is versatile and dynamic depending on its protein interactions. Here, using a BioID approach we identified the NE protein, Nesprin-3, as a novel Emerin interactor in mKRAS pancreatic cancer cells. Transcriptomic and epigenomic analyses revealed that mKRAS increases Nesprin-3 expression using the transcription factor KLF5 as an effector. Functional studies demonstrated that Nesprin-3 phenocopies Emerin, where knockdown of Nesprin-3 impaired nuclear morphology, proliferation, and gene expression changes induced by mKRAS. Notably, Nesprin-3 overexpression can rescue the nuclear morphology and proliferative phenotype in pancreatic cancer cells with mKRAS knockdown. Finally, utilizing an Emerin mutant that cannot interact with Nesprin-3 we failed to rescue these nuclear size changes. Our data demonstrate a novel mechanism underlying the oncogenic function of KRAS, a major driver of this dismal condition.
Insights
Oncogenic mutant KRAS (mKRAS) alters pancreatic cancer cell nuclear size by increasing Nesprin-3 expression, which is essential for nuclear morphology and proliferation.
Area of Science:
- Cell Biology
- Cancer Biology
- Molecular Oncology
Background:
- Nuclear envelope (NE) proteins are crucial for nuclear morphology and cellular phenotypes.
- Their roles in cancer, particularly pancreatic cancer, are not well understood.
- Oncogenic mutant KRAS (mKRAS) is known to alter nuclear size during pancreatic transformation.
Purpose of the Study:
- To investigate the NE proteins involved in mKRAS-driven nuclear morphology changes in pancreatic cancer.
- To identify novel interactors of Emerin in mKRAS pancreatic cancer cells.
- To elucidate the mechanism by which mKRAS influences nuclear morphology and proliferation.
Main Methods:
- BioID proximity labeling to identify NE protein interactors.
- Transcriptomic and epigenomic analyses to study gene expression.
- Functional studies including knockdown and overexpression of Nesprin-3.
- Utilizing Emerin mutants to assess interaction-dependent rescue.
Main Results:
- Nesprin-3 was identified as a novel Emerin interactor in mKRAS pancreatic cancer cells.
- mKRAS upregulates Nesprin-3 expression via the transcription factor KLF5.
- Nesprin-3 knockdown phenocopied Emerin, impairing nuclear morphology, proliferation, and gene expression.
- Nesprin-3 overexpression rescued mKRAS-induced nuclear and proliferative defects.
- Emerin mutants unable to interact with Nesprin-3 failed to rescue nuclear size changes.
Conclusions:
- Nesprin-3 is a key mediator of mKRAS-driven nuclear morphology and proliferation in pancreatic cancer.
- The mKRAS-Emerin-Nesprin-3 axis represents a novel mechanism in pancreatic oncogenesis.
- Targeting this pathway may offer therapeutic strategies for pancreatic cancer.
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