PRL-3 promotes ubiquitination and degradation of AURKA and colorectal cancer progression via dephosphorylation of FZR1

The oncogenic phosphatase PRL-3 is highly expressed in metastatic colorectal cancer (CRC) but not in non-metastatic CRC or non-CRC metastatic cancers. Although the pro-invasive capacity of PRL-3 has been validated in multiple types of cancer, its impact on CRC progression and the underlying mechanisms remain poorly understood. Here we report that overexpressed PRL-3 stimulates G2/M arrest, chromosomal instability (CIN), self-renewal, and growth of CRC cells in xenograft models, while CRC cell proliferation is decreased. PRL-3-induced G2/M arrest was associated with decreased expression of Aurora kinase A (AURKA). PRL-3-promoted slow proliferation, CIN, self-renewal, and growth in xenografts were counteracted by ectopic expression of AURKA. Conversely, knockdown of PRL-3 resulted in low proliferation, S-phase arrest, impaired self-renewal, increased apoptosis, and diminished xenograft growth independently of AURKA. Analysis of CRC specimens showed that expression of PRL-3 was associated with high status of CIN and poor prognosis, which were antagonized by expression of AURKA. PRL-3 enhanced AURKA degradation and ubiquitination in a phosphatase-dependent fashion. PRL-3 interacted with AURKA and FZR1, a regulatory component of the APC/CFZR1 complex. Destabilization of AURKA by PRL-3 required PRL-3-mediated dephosphorylation of FZR1 and assembly of the APC/CFZR1 complex. Our study suggests that PRL-3-regulated CRC progression is collectively determined by distinct malignant phenotypes and further reveals PRL-3 as an essential regulator of APC/CFZR1 in controlling the stability of AURKA.