The role of centrosomal protein of 295 kDa (CEP295) in cellular function and hepatocarcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is one of the leading cancers around the world and responsible for 800 thousand deaths in 2020. Existing standard therapies for HCC provide limited effect and the 5-year recurrence rate is high. Viral infections, excessive alcohol use, contaminated food ingestion and metabolic diseases are identified risk factors for HCC. At molecular level, genes govern the cell cycle regulation, apoptosis and telomere maintenance are altered in the progression of HCC. Such alterations can be caused by dysregulated expression level or mutation at functional domains, whereas chromosome instability (CIN) is accounted for these genetic modifications. Profound CIN was observed in early HCC samples, suggesting a link between CIN and HCC development. CIN is a consequent of error-mediated chromosome segregation, whereas authentic centrosome is required for precise chromosome segregation. Centrosome is known as a microtubule organizing center (MTOC) governs numerous important cellular functions, including cell proliferation, migration and differentiation. Centrosomal protein of 295 kDa (CEP295) is discovered as an important centriole building block and plays an important role in centriole-to centrosome conversion. However, the role of CEP295 in HCC formation and the assembly of centrioles remains unexplored. In this study, the centriolar architecture in close proximity to CEP295 were revealed with sub-super-resolution microscopy. The distribution of CEP295 and its adjacent centriolar proteins was conserved across mammalian cells and retained even upon centrosome aberration. It suggested the centrosome core structure was tightly regulated and intolerant to disruption. To examine the potential role of CEP295 in hepatocarcinogenesis, functional cell assays were performed with CEP295 knocked down. Both cell proliferation and migration were impaired suggesting CEP295 was likely to be oncogenic in HCC development. Since CEP295 harbors two microtubule binding domains on its N- and C-terminus, the impact of CEP295 on microtubule dynamic was studied. To uncover the function of CEP295, deletion mutants of CEP295 were examined for oncogenic properties and cellular distribution. Surprisingly, CEP295 was found to accumulate at the central spindle during cytokinesis through its C-terminal microtubule binding domain. This indicated CEP295 may involve the cytokinesis progression, in particular the cell abscission, and provided an insight to CEP295 non-centriolar function. In summary, CEP295 is a centriolar core protein that forms stable centrosome structure. It promotes HCC cell proliferation and migration, and regulates microtubule dynamic. Additionally, the microtubule binding domain targeted CEP295 to the central spindle and the function warrants further investigation.