PRL-3 Promotes Ubiquitination and Degradation of AURKA and Colorectal Cancer Progression via Dephosphorylation of FZR1

Abstract

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 G 2 -M arrest, chromosomal instability (CIN), self-renewal, and growth of colorectal cancer cells in xenograft models, while colorectal cancer cell proliferation is decreased. PRL-3induced G 2 -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 colo-rectal 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 phosphatasedependent fashion. PRL-3 interacted with AURKA and FZR1, a regulatory component of the APC/C FZR1 complex. Destabilization of AURKA by PRL-3 required PRL-3-mediated dephosphorylation of FZR1 and assembly of the APC/C FZR1 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/C FZR1 in controlling the stability of AURKA.Significance: Dephosphorylation of FZR1 by PRL-3 facilitates the activity of APC/C FZR1 by destabilizing AURKA, thus influencing aggressive characteristics and overall progression of colorectal cancer.

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

“…VHL is an E3 ligase that multimonoubiquitinates AURKA in quiescent cells and targets it for proteasome-mediated degradation under both normoxic and hypoxic conditions [38]. Phosphatase PRL-3 enhances AURKA ubiquitination and degradation in colorectal cancer [34]. Destabilization of AURKA by PRL-3 requires PRL-3-mediated dephosphorylation of FZR1 and assembly of the APC/CFZR1 complex [34].…”

“…Phosphatase PRL-3 enhances AURKA ubiquitination and degradation in colorectal cancer [34]. Destabilization of AURKA by PRL-3 requires PRL-3-mediated dephosphorylation of FZR1 and assembly of the APC/CFZR1 complex [34]. PTPRD is a protein tyrosine phosphatase and a tumor suppressor.…”

Identifying Potential Prognostic Biomarkers Associated With Clinicopathologic Characteristics of Hepatocellular Carcinoma by Bioinformatics Analysis

“…AURKA has been defined as a crucial regulator of mitotic chromosome segregation through its catalytic activity [42,43]. The oncogenic phosphatase PRL-3 is upregulated in metastatic colorectal cancer and it interacted with AURKA and FZR1, thus influencing the development of colorectal cancer [44]. It was reported that thiostrepton could reduce FOXM1 target genes expression including AURKA and CCNB1, which contributed to the progression of G2/M cell cycle [45].…”

FZR1 as a novel biomarker for breast cancer neoadjuvant chemotherapy prediction

“…FZR1 is considered as a tumor suppressor that are negatively regulated the activation of the MEK/ERK oncogenic signaling cascade 48 . The evidence showed that FZR1 interacted with PRL-3 to regulate the progression of colorectal cancer by controlling the stability of AURKA 49 . These results are consistent with our clinical validation that the expression of FZR1 is correlated with the prognosis and survival of breast cancer patients.…”