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A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression.

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.
AuthorsWei-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
JournalCancer cell (Cancer Cell) Vol. 20 Issue 2 Pg. 214-28 (Aug 16 2011) ISSN: 1878-3686 [Electronic] United States
PMID21840486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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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