Abstract
Neuroblastoma (NB) is a devastating malignancy threatening children’s health, and amplification of MYCN is associated with treatment failure and a poor outcome. Here, we aimed to demonstrate the role of cell division cycle 27 (CDC27), an important core subunit of the anaphase-promoting complex, and its clinical significance in NB patients. In functional assays, we illustrated that CDC27 promoted the cell growth, metastasis and sphere-formation ability of NB cells both in vitro and in vivo. To further understand the potential mechanism, SK-N-SH cells were transfected with CDC27 siRNA, and RNA-sequencing was performed. The results revealed that downregulation of CDC27 led to markedly reduced expression of ODC1, which is a well-established direct target of MYCN. Subsequently, we further illustrated that suppression of ODC1 significantly attenuated the promotion effect of CDC27 on the proliferation, metastasis, and sphere-formation ability of NB cells, hinting that CDC27 exerted its biological behavior in NB at least partly in an ODC1-dependent manner. In addition, CDC27 rendered cells more vulnerable to ferroptosis, while knockdown of ODC1 markedly reversed the pro-ferroptotic effect of CDC27. Collectively, our data is the first to report that the CDC27/ODC1 axis promotes tumorigenesis and acts as a positive regulator of ferroptosis in NB, highlighting that CDC27 may represent a novel therapeutic strategy and prognostic biomarker in neuroblastoma.
Highlights
Neuroblastoma (NB) is a peripheral neural system tumor that derives from the primitive neural crest
The results indicated that Cell division cycle 27 (CDC27) was frequently upregulated in NB cell lines compared with normal dorsal root ganglion cells (Figure S1B)
The results revealed that the expression of CDC27 is related to the malignancy degree of NB, because CDC27 expression was markedly increased in NB and GNB tissues compared with GN tissues (NB+GNB n=96, GN n=25; Figures 1A, B), and higher in stage 3-4 NB patients than in stage 1-2 NB patients (Figure 1C)
Summary
Neuroblastoma (NB) is a peripheral neural system tumor that derives from the primitive neural crest. High-risk NB is always characterized by amplification of MYCN, which is associated with treatment failure and indicates an extremely poor outcome [1,2,3,4]. Considerable efforts have been concentrated on the critical target genes and pathways of MYCN, such as ODC1, TERT, ID2, and polyamine pathways [7,8,9,10,11,12]. We have reported that CDC27 promoted tumor progression and served as an independent prognostic factor in colorectal cancer [17, 18]. There is evidence indicating that CDC27 may act as a tumor suppressor in breast cancer [19]. The role of CDC27 in NB still remains unknown
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