A Cullin3-KLHL20 Ubiquitin Ligase-Dependent Pathway Targets PML to Potentiate HIF-1 Signaling and Prostate Cancer Progression
Journal
Cancer Cell
Journal Volume
20
Journal Issue
2
Pages
214-228
Date Issued
2011
Author(s)
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.
Jou Y.-S.
Lu K.
Hsiao P.-W.
Shih H.-M.
Chen R.-H.
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. ? 2011 Elsevier Inc.
SDGs
Other Subjects
cullin 3; cyclin dependent kinase 1; cyclin dependent kinase 2; hypoxia inducible factor 1; hypoxia inducible factor 1alpha; peptidylprolyl isomerase Pin1; promyelocytic leukemia protein; protein klhl20; ubiquitin protein ligase; unclassified drug; angiogenesis; animal experiment; animal model; article; cell migration; down regulation; epithelial mesenchymal transition; gene expression; gene overexpression; human; human cell; human tissue; hypoxia; isomerization; male; mouse; nonhuman; priority journal; prostate cancer; protein degradation; protein function; protein phosphorylation; protein protein interaction; signal transduction; tumor growth; ubiquitination; upregulation
Type
journal article