Recently, migration and invasion of breast cancer cells have been linked with dysregulated mitochondrial dynamics. Mitochondria are essential cellular organelles that undergo continuous dynamic cycles of fission and fusion. It has been proposed that a delicate balance between these two processes is important for many pathophysiological outcomes including cancer. Epstein-Barr virus (EBV) is a gamma herpesvirus that is associated with various lymphoid and epithelial malignancies. The viral latent membrane protein 2A (LMP2A) has been shown to increase the invasive ability and induce epithelial-mesenchymal transition in nasopharyngeal carcinoma. Our present study reveals that mitochondrial dynamics also plays a critical role in Epstein-Barr virus-associated epithelial cancers. Our data indicate that viral LMP2A causes an elevated mitochondrial fission in gastric and breast cancer cells, which is manifested by elevated fission protein dynamin-related protein 1 (Drp1). Furthermore, LMP2A-mediated Notch pathway is responsible for this enhanced fission since inhibitors of the pathway decrease the expression of Drp1.

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Notch pathway is a well-known factor in the development of lymphoid lineage. However, its role in the myeloid lineage has remained ambiguous. We looked into the effect of Notch1 on the megakaryocytic lineage commitment and found an increase in megakaryocyte-specific lineage markers upon transfection with Notch1 intracellular domain (NICD). This effect was mediated by Akt whereby constitutive activation of Akt increased the megakaryocyte markers, whereas inhibition of Akt signalling reduced these marker levels. Along with the change in differentiation status, NICD-induced initiation of early megakaryopoiesis was accompanied by an increased cytoplasmic enhancer of zeste homolog-2 (EZH2) expression. This process was found to be Akt-dependent, and inhibition or overexpression of Akt lead to concurrent changes in EZH2 levels. To elucidate the function of EZH2 in the cytoplasm, novel cytoplasmic interactors of EZH2 were identified by co-immunoprecipitation followed by matrix-assisted laser desorption ionization MS/MS-based protein identification, and thus, PDIA1 and LIM domain kinase-1 (LIMK1) were identified. Interaction of EZH2 with LIMK1 changed the activity of cofilin (a downstream target of LIMK1) towards actin filaments, thereby leading to lower filamentous actin content within these cells. Thus, Notch1 not only induces early megakaryopoiesis but also prepares these cells for subsequent morphological changes.

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