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.YEONG-SHIAU PUJou Y.-S.Lu K.Hsiao P.-W.Shih H.-M.Chen R.-H.2021-02-022021-02-0220111535-6108https://www.scopus.com/inward/record.uri?eid=2-s2.0-80051583598&doi=10.1016%2fj.ccr.2011.07.008&partnerID=40&md5=fcf8776c06b29821cd06a8679f34a406https://scholars.lib.ntu.edu.tw/handle/123456789/544422Tumor 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]SDG3cullin 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; upregulationjournal article10.1016/j.ccr.2011.07.008218404862-s2.0-80051583598