A Novel Emerin/Nesprin-3 Interaction Mediates Nuclear Size Changes Induced by Oncogenic KRAS in Pancreatic Cancer Cells.

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.