Author/Authors :
Yuan، نويسنده , , Wei-Chien and Lee، نويسنده , , Yu-Ru and Huang، نويسنده , , Shiu-Feng and Lin، نويسنده , , Yu-Min and Chen، نويسنده , , Tzu-Yin and Chung، نويسنده , , Hsiang-Ching and Tsai، نويسنده , , Chin-Hsien and Chen، نويسنده , , Hsin-Yi and Chiang، نويسنده , , Cheng-Ta and Lai، نويسنده , , Chun-Kai and Lu، نويسنده , , Li-Ting and Chen، نويسنده , , Chun-Hau and Gu، نويسنده , , De-Leung and Pu، نويسنده , , Yeong-Shiau and Jou، نويسنده , , Yuh-Shan and Lu، نويسنده , , Kun Ping and Hsiao، نويسنده , , Pei-Wen and Shih، نويسنده , , Hsiu-Ming and Chen، نويسنده , , Ruey-Hwa، نويسنده ,
Abstract :
Summary
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.
