A Cullin3-KLHL20 Ubiquitin Ligase-Dependent Pathway Targets PML to Potentiate HIF-1 Signaling and Prostate Cancer Progression

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

Research output: Contribution to journalArticle

96 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)214-228
Number of pages15
JournalCancer Cell
Volume20
Issue number2
DOIs
Publication statusPublished - Aug 16 2011
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Yuan, W. C., Lee, Y. R., Huang, S. F., Lin, Y. M., Chen, T. Y., Chung, H. C., Tsai, C. H., Chen, H. Y., Chiang, C. T., Lai, C. K., Lu, L. T., Chen, C. H., Gu, D. L., Pu, Y. S., Jou, Y. S., Lu, K. P., Hsiao, P. W., Shih, H. M., & Chen, R. H. (2011). A Cullin3-KLHL20 Ubiquitin Ligase-Dependent Pathway Targets PML to Potentiate HIF-1 Signaling and Prostate Cancer Progression. Cancer Cell, 20(2), 214-228. https://doi.org/10.1016/j.ccr.2011.07.008