Abstract
BackgroundGliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma.MethodsTo investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model.ResultsSkp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo.ConclusionOur data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.
Highlights
Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses
High expression level of S-phase kinase-associated protein 2 (Skp2) predicted a poor prognosis in glioma Based on the RNA sequencing data from TCGA and GTEx, the web-based tool Gene Expression Profiling Interactive Analysis (GEPIA), helped us analyzing the expression of the genes [13]
IDH1 mutation was a favorable factor in the prognosis of diffuse glioma especially in low-grade glioma (LGG) based on the 2016 WHO classification [19]
Summary
Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. Efficient ways to improve the long-term prognosis of patients, such as overcoming TMZ resistance, are urgently required. To this end, the S-phase kinase-associated protein 2 (Skp2) has been identified as a potential prospect worth investigating. The mRNA level of Skp was found increased in triple-negative breast cancer (TNBC) and was significantly associated with poor prognoses, and its suppression in TNBC inhibited cell proliferation and G1/S transition; evincing Skp as a protooncoprotein
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