2. Academic Validation
  3. 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

  • Cancer Cell. 2011 Aug 16;20(2):214-28. doi: 10.1016/j.ccr.2011.07.008.
Wei-Chien Yuan 1,  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
Affiliations

Affiliation

  • 1 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
PMID: 21840486 DOI: 10.1016/j.ccr.2011.07.008
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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