CDC20 maintains tumor initiating cells.
CDC20 maintains tumor initiating cells.
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DOI：
10.18632/oncotarget.3676
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发表时间：
2015-05-30
期刊：
影响因子：
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通讯作者：
Rich JN
中科院分区：
文献类型：
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作者：
Xie Q;Wu Q;Mack SC;Yang K;Kim L;Hubert CG;Flavahan WA;Chu C;Bao S;Rich JN
胶质母细胞瘤是最常见和最致命的原发性脑肿瘤。胶质母细胞瘤显示分层排列与群体自我更新和致瘤性胶质瘤肿瘤起始细胞（tic），或癌症干细胞。非肿瘤性神经干细胞通常是静止的，而胶质母细胞瘤的tic通常是增殖的，有丝分裂控制提供了一个潜在的脆弱性点。在这里，我们探讨了细胞分裂周期蛋白20 （CDC20）在维持tic中的作用，CDC20是后期促进复合体（APC） E3泛素化连接酶的重要激活剂。通过染色质分析和免疫印迹，CDC20在tic中相对于匹配的非tic优先表达。通过RNA干扰靶向CDC20表达可减弱TIC增殖、自我更新和体内肿瘤生长。CDC20破坏通过诱导细胞凋亡和抑制细胞周期进程介导其作用。CDC20通过降解p21CIP1/WAF1维持tic， p21CIP1/WAF1是tic的关键负调节因子。抑制CDC20可以稳定p21CIP1/WAF1，从而抑制对肿瘤生长和生存至关重要的几个基因，包括CDC25C、c-Myc和Survivin。CDC20的转录控制是由tic的中心转录因子FOXM1介导的。这些结果表明，CDC20是TIC增殖和存活的关键调节因子，连接两个关键的TIC节点- FOXM1和p21CIP1/WAF1 -阐明了治疗干预的潜在点。
Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor. Glioblastoma displays hierarchical arrangement with a population of self-renewing and tumorigenic glioma tumor initiating cells (TICs), or cancer stem cells. While non-neoplastic neural stem cells are generally quiescent, glioblastoma TICs are often proliferative with mitotic control offering a potential point of fragility. Here, we interrogate the role of cell-division cycle protein 20 (CDC20), an essential activator of anaphase-promoting complex (APC) E3 ubiquitination ligase, in the maintenance of TICs. By chromatin analysis and immunoblotting, CDC20 was preferentially expressed in TICs relative to matched non-TICs. Targeting CDC20 expression by RNA interference attenuated TIC proliferation, self-renewal and in vivo tumor growth. CDC20 disruption mediated its effects through induction of apoptosis and inhibition of cell cycle progression. CDC20 maintains TICs through degradation of p21CIP1/WAF1, a critical negative regulator of TICs. Inhibiting CDC20 stabilized p21CIP1/WAF1, resulting in repression of several genes critical to tumor growth and survival, including CDC25C, c-Myc and Survivin. Transcriptional control of CDC20 is mediated by FOXM1, a central transcription factor in TICs. These results suggest CDC20 is a critical regulator of TIC proliferation and survival, linking two key TIC nodes – FOXM1 and p21CIP1/WAF1 — elucidating a potential point for therapeutic intervention.