Abstract |
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-1α 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-1α, 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-1α autoregulation play key roles in tumor progression.
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Authors | Wei-Chien Yuan, Yu-Ru Lee, Shiu-Feng Huang, Yu-Min Lin, Tzu-Yin Chen, Hsiang-Ching Chung, Chin-Hsien Tsai, Hsin-Yi Chen, Cheng-Ta Chiang, Chun-Kai Lai, Li-Ting Lu, Chun-Hau Chen, De-Leung Gu, Yeong-Shiau Pu, Yuh-Shan Jou, Kun Ping Lu, Pei-Wen Hsiao, Hsiu-Ming Shih, Ruey-Hwa Chen |
Journal | Cancer cell
(Cancer Cell)
Vol. 20
Issue 2
Pg. 214-28
(Aug 16 2011)
ISSN: 1878-3686 [Electronic] United States |
PMID | 21840486
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Inc. All rights reserved. |
Chemical References |
- Adaptor Proteins, Signal Transducing
- Carrier Proteins
- Cullin Proteins
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- KLHL20 protein, human
- Ubiquitin-Protein Ligases
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Topics |
- Adaptor Proteins, Signal Transducing
- Animals
- Carrier Proteins
(metabolism)
- Cell Line
- Cullin Proteins
(physiology)
- Disease Progression
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Male
- Mice
- Prostatic Neoplasms
(physiopathology)
- Ubiquitin-Protein Ligases
(metabolism)
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