Abstract
Glioma stem-like cells (GSCs) are a subset of tumor cells that initiate malignant growth and promote the therapeutic resistance of glioblastoma, the most lethal primary brain tumor. Ribosome biogenesis is an essential cellular process to maintain cell growth, but its regulatory mechanism in GSCs remains largely unknown. Here, we show that WD repeat domain 12 (WDR12), a component of the Pes1-Bop1 complex (PeBoW), is required for ribosome biogenesis in GSCs. WDR12 is preferentially expressed in GSCs compared to non-stem tumor cells and normal brain cells. High levels of WDR12 are associated with glioblastoma progression and poor prognosis. Silencing WDR12 results in the degradation of PeBoW complex components and prevents the maturation of 28S rRNA, thereby inhibiting ribosome biogenesis in GSCs. Subsequently, WDR12 depletion compromises GSC proliferation, inhibits GSC-derived orthotopic tumor growth, and extends animal survival. Together, our results suggest that WDR12 is crucial for ribosome biogenesis in GSCs, and is thus a potential target for GSC-directed therapy of glioblastoma.
Highlights
Glioblastoma multiforme (GBM) ranks among the most aggressive and lethal of human brain tumors with dismal prognoses
In our previous mass spectrometry screen, we identified a series of proteins, including with tryptophan–aspartic acid (WD) repeat domain 12 (WDR12), that were highly expressed in glioma stem-like cells (GSCs) compared to those in non-stem tumor cells (NSTCs) [24]
We found that the levels of WDR12 were gradually decreased during Glioma stem-like cells (GSCs) differentiation induced by serum treatment (Figure 1C)
Summary
Glioblastoma multiforme (GBM) ranks among the most aggressive and lethal of human brain tumors with dismal prognoses. Studies show that GSCs contribute to therapeutic resistance and tumor recurrence of gliomas, suggesting that targeting GSCs may be a promising strategy to improve GBM treatment [4,5,6,7]. The ribosome is one of the oldest molecular machines It is composed of distinct proteins and nucleic acids and is responsible for protein synthesis in every living cell. The human 80S ribosome is composed of a large 60S subunit that harbors the 28S, 5.8S, and 5S rRNAs plus 47 proteins, and a small 40S subunit that contains the 18S rRNA and 33 proteins. It is wellestablished that increased ribosome biogenesis and protein synthesis are required for sustaining tumor cell growth and proliferation [8, 10]. The molecular mechanism by which ribosomal biogenesis is regulated in GSCs remains largely unclear
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