The heterogeneous nature of cancer is promoted by elevated levels of aneuploidy caused by genomic instability (GIN), which predisposes cells to malignant transformation. Cep55, a protein initially characterised by our laboratory as a cytokinesis regulator has also been shown to be an important regulator of GIN, and its overexpression correlates with aggressiveness, metastasis and poor prognosis in many tumour types. Moreover, our lab recently showed that loss of Cep55 sensitizes cancer cells to anti-mitotic agents, which could be a potential therapeutic strategy against Cep55-overexpressing tumours. Perturbation of CEP55 levels in in vitro studies has also highlighted its roles in PI3K/Akt regulation, midbody fate and stemness.
To better understand the role of Cep55 in the cancer context, we generated the first Cep55 Knockout (KO) mouse model. Interestingly, homozygous loss of Cep55 was late embryonically lethal, indicating a crucial physiological role in embryonic development. To understand the molecular causes underpinning this phenotype, we established mouse embryonic fibroblasts (MEFs) from Cep55 WT and KO embryos. This in-vitro model revealed increased cytokinesis failure leading to multinucleated cells and decreased proliferation in Cep55 KO MEFs, as a consequence of mitotic defects. To determine if Cep55 loss would perturb transformation ability, we transformed Cep55 WT and KO MEFs with E1A/Ras oncogenes. Strikingly, we found that anchorage‐independent colony formation was reduced upon E1A/Ras Cep55 KO in colony formation assay and 3D culture. Similarly, loss of Cep55 abrogated tumour formation in NOD/SCID mice injected sub-cutaneously with with E1A/Ras-transformed Cep55 KO MEFs, suggesting that CEP55 is essential for proper tumour formation. Immunoblotting of Cep55 WT and KO MEFs revealed roles of Cep55 in regulating GSK3β/ β-Catenin/Myc signalling, which may contribute to its role in regulating tumour formation. Altogether, our data suggests preliminary mechanistic evidence of Cep55 contribution to tumorigenesis through the GSK3β/ β-Catenin/ myc axis and Cep55 may be a useful molecular target to prevent the initiation and progression of cancer.