Abstract
Simple SummaryGroup 3 medulloblastoma (MB) is often accompanied by MYC amplification and has a poor prognosis. FBXW7, a critical tumor suppressor in many types of cancer, regulates the proteasome-mediated degradation of oncoproteins including MYC. However, the role of FBXW7 in the tumorigenesis of group 3 MB has not been well studied. In this study, we show that FBXW7 is downregulated in group 3 MB patient samples, and FBXW7 stabilization is crucial for inhibiting c-MYC. We identified a FBXW7-MYC-PLK1 regulatory loop in MYC-driven MB, which provides a mechanism of using protein kinase inhibitors for translation in the future.Polo-like kinase 1 (PLK1) is highly expressed in group 3 medulloblastoma (MB), and it has been preclinically validated as a cancer therapeutic target in medulloblastoma. Here, we demonstrate that PLK1 inhibition with PCM-075 or BI6727 significantly reduces the growth of MB cells and causes a decrease of c-MYC mRNA and protein levels. We show that MYC activates PLK1 transcription, while the inhibition of PLK1 suppresses MB tumor development and causes a decrease in c-MYC protein level by suppressing FBXW7 auto poly-ubiquitination. FBXW7 physically interacts with PLK1 and c-MYC, facilitating their protein degradation by promoting ubiquitination. These results demonstrate a PLK1-FBXW7-MYC regulatory loop in MYC-driven medulloblastoma. Moreover, FBXW7 is significantly downregulated in group 3 patient samples. The overexpression of FBXW7 induced apoptosis and suppressed proliferation in vitro and in vivo, while constitutive phosphorylation mutation attenuated its tumor suppressor function. Altogether, these findings demonstrated that PLK1 inhibition stabilizes FBXW7 in MYC-driven MB, thus revealing an important function of FBXW7 in suppressing medulloblastoma progression.
Highlights
Brain tumors are the most common cause of oncological death in children, and medulloblastoma (MB) is a malignant childhood brain tumor, accounting for 20–25% of pediatric brain tumors [1,2,3]
To evaluate the mechanisms by which Polo-like kinase 1 (PLK1) is overexpressed in MYC-driven medulloblastoma, we first asked whether c-MYC activates PLK1 transcription in medulloblastoma
Microarray results showed that the expression of c-MYC and PLK1 was positively correlated in medulloblastoma (Figure 1a,b)
Summary
Brain tumors are the most common cause of oncological death in children, and medulloblastoma (MB) is a malignant childhood brain tumor, accounting for 20–25% of pediatric brain tumors [1,2,3]. We and others have previously identified PLK1 as a key regulator of medulloblastoma cell viability [12,13] Despite considerable study, it is not yet clear why the expression of PLK1 is upregulated and how a high level of PLK1 reprograms cells to promote the cancer state in medulloblastoma. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin–proteasome system proteins in human cancer [17,18,19]. It is a component of the SCF-like ubiquitin ligase complex that targets MYC for proteasomal degradation. Our results reveal a PLK1-FBXW7-MYC signaling circuit that underlies tumor pathogenesis and provide a potential strategy for the activation of FBXW7 against c-MYC-driven MB
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