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
  • 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.