A Cullin3-KLHL20 Ubiquitin Ligase-Dependent Pathway Targets PML to Potentiate HIF-1 Signaling and Prostate Cancer Progression
A Cullin3-KLHL20 Ubiquitin Ligase-Dependent Pathway Targets PML to Potentiate HIF-1 Signaling and Prostate Cancer Progression
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DOI：
10.1016/j.ccr.2011.07.008
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发表时间：
2011-08-16
期刊：
影响因子：
50.3
通讯作者：
Chen, Ruey-Hwa
中科院分区：
文献类型：
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作者：
Yuan, Wei-Chien;Lee, Yu-Ru;Chen, Ruey-Hwa
肿瘤缺氧与疾病进展和治疗失败相关，但缺氧信号机制尚未完全了解。在这里，我们表明，KLHL 20，一个Cullin 3（Cul 3）底物适配器诱导的HIF-1，协调与CDK 1/2和Pin 1的行动，介导缺氧诱导的PML蛋白酶体降解。此外，这种PML破坏途径参与反馈机制以最大化HIF-1 α诱导，从而增强多种肿瘤缺氧反应，包括代谢重编程、上皮-间质转化、迁移、肿瘤生长、血管生成和化疗耐药性。在人前列腺癌中，HIF-1 α、KLHL 20和Pin 1的过表达与PML下调相关，而PML破坏途径的过度活化与疾病进展相关。我们的研究表明，KLHL 20介导的PML降解和HIF-1 α自身调节在肿瘤进展中起关键作用。
Tumor hypoxia is associated with disease progression and treatment failure, but the hypoxia signaling mechanism is not fully understood. Here, we show that KLHL20, a Cullin3 (Cul3) substrate adaptor induced by HIF-1, coordinates with the actions of CDK1/2 and Pin1 to mediate hypoxia-induced PML proteasomal degradation. Furthermore, this PML destruction pathway participates in a feedback mechanism to maximize HIF-1 alpha induction, thereby potentiating multiple tumor hypoxia responses, including metabolic reprogramming, epithelial-mesenchymal transition, migration, tumor growth, angiogenesis, and chemoresistance. In human prostate cancer, overexpression of HIF-1 alpha, KLHL20, and Pin1 correlates with PML down-regulation, and hyperactivation of the PML destruction pathway is associated with disease progression. Our study indicates that the KLHL20-mediated PML degradation and HIF-1 alpha autoregulation play key roles in tumor progression.