NEK8 stabilization via USP51-mediated deubiquitination promotes colorectal cancer progression

NEK8 is a kinase involved in diverse cellular processes. Accumulating evidence has demonstrated that NEK8 contributes to the development of colorectal cancer (CRC). However, the regulation of its protein stability is poorly understood. Deubiquitinases, such as USP51, can keep protein levels stable by cleaving ubiquitin chains off. In this study, GEO analysis demonstrated elevated expression of USP51, while NEK8 mRNA levels showed no significant difference between CRC tissues and adjacent normal tissues, indicating post-transcriptional regulation. Immunohistochemistry showed a high expression of both NEK8 and USP51 proteins in cancer tissues and a positive correlation between them. Tissue microarray assay verified that NEK8 is an independent risk factor for CRC. In vitro functional experiments confirmed that NEK8 and USP51 promoted proliferation, colony formation, invasion, and migration of CRC, and a subcutaneous tumor formation assay further verified the oncogenic function of NEK8. Co-immunoprecipitation, co-immunofluorescence, ubiquitination assays, and functional rescue experiments proved that USP51 directly interacted with NEK8 and lowered the ubiquitination level of NEK8. Functional enrichment assays demonstrated that NEK8 modulates the WNT/β-catenin pathway. The knockdown of NEK8 resulted in decreased β-catenin protein levels. Taken together, our study reveals that the USP51-NEK8 axis promotes progression of CRC via the β-catenin pathway and could be a potential target for the treatment of CRC.