Mi Lanjuan, Qi Qinghui, Ran Haowen, Chen Lishu, Li Da, Xiao Dake, Wu Jiaqi, Cai Yan, Zhang Songyang, Li Yuanyuan, Li Bohan, Xie Jiong, Huang Haohao, Li Tao, Zhou Tao, Li Ailing, Qi Ji, Li Fangye, Man Jianghong
State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing, China.
Department of Neurosurgery, Beijing Fengtai Hospital, Beijing, China.
Front Oncol. 2021 Nov 12;11:751792. doi: 10.3389/fonc.2021.751792. eCollection 2021.
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.
胶质瘤干细胞（GSCs）是一类肿瘤细胞亚群，可引发恶性生长并增强胶质母细胞瘤（最致命的原发性脑肿瘤）的治疗抗性。核糖体生物合成是维持细胞生长的关键细胞过程，但其在胶质瘤干细胞中的调控机制仍基本未知。在此，我们表明WD重复结构域12（WDR12），即Pes1-Bop1复合物（PeBoW）的一个组成部分，是胶质瘤干细胞核糖体生物合成所必需的。与非干细胞肿瘤细胞和正常脑细胞相比，WDR12在胶质瘤干细胞中优先表达。高水平的WDR12与胶质母细胞瘤进展及不良预后相关。沉默WDR12会导致PeBoW复合物成分降解，并阻止28S rRNA成熟，从而抑制胶质瘤干细胞中的核糖体生物合成。随后，WDR12缺失损害胶质瘤干细胞增殖，抑制胶质瘤干细胞原位肿瘤生长，并延长动物生存期。总之，我们的结果表明WDR12对胶质瘤干细胞的核糖体生物合成至关重要，因此是胶质母细胞瘤靶向胶质瘤干细胞治疗的潜在靶点。
