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 but not in nonmetastatic colorectal cancer or noncolorectal cancer metastatic cancers. Although the proinvasive capacity of PRL-3 has been validated in multiple types of cancer, its impact on colorectal cancer 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 colorectal cancer cells in xenograft models, while colorectal cancer 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 colorectal cancer 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 ubiquitination and degradation 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 colorectal cancer 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. SIGNIFICANCE: Dephosphorylation of FZR1 by PRL-3 facilitates the activity of APC/CFZR1 by destabilizing AURKA, thus influencing aggressive characteristics and overall progression of colorectal cancer.
Mesh Terms:
Animals, Aurora Kinase A, Cdh1 Proteins, Cell Line, Tumor, Colorectal Neoplasms, Disease Progression, Female, G2 Phase Cell Cycle Checkpoints, HCT116 Cells, HT29 Cells, HeLa Cells, Heterografts, Humans, M Phase Cell Cycle Checkpoints, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Proteins, Phosphorylation, Proteasome Endopeptidase Complex, Protein Tyrosine Phosphatases, Ubiquitin, Ubiquitination
Animals, Aurora Kinase A, Cdh1 Proteins, Cell Line, Tumor, Colorectal Neoplasms, Disease Progression, Female, G2 Phase Cell Cycle Checkpoints, HCT116 Cells, HT29 Cells, HeLa Cells, Heterografts, Humans, M Phase Cell Cycle Checkpoints, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Proteins, Phosphorylation, Proteasome Endopeptidase Complex, Protein Tyrosine Phosphatases, Ubiquitin, Ubiquitination
Cancer Res.
Date: Dec. 01, 2018
PubMed ID: 30498084
View in: Pubmed Google Scholar
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