title: A Cullin3-KLHL20 Ubiquitin ligase-dependent pathway targets PML to potentiate HIF-1 signaling and prostate cancer progression.
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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Yuan
authors.forename: Yu-Ru
authors.initials: YR
authors.lastname: Lee
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Lin
authors.forename: Tzu-Yin
authors.initials: TY
authors.lastname: Chen
authors.forename: Hsiang-Ching
authors.initials: HC
authors.lastname: Chung
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Tsai
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Cheng-Ta
authors.initials: CT
authors.lastname: Chiang
authors.forename: Chun-Kai
authors.initials: CK
authors.lastname: Lai
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Lu
authors.forename: Chun-Hau
authors.initials: CH
authors.lastname: Chen
authors.forename: De-Leung
authors.initials: DL
authors.lastname: Gu
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.forename: Yuh-Shan
authors.initials: YS
authors.lastname: Jou
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hsiao
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: Ruey-Hwa
authors.initials: RH
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D044842:Cullin Proteins / Q000502:physiology*; D018450:Disease Progression; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D044842:Cullin Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C550011:KLHL20 protein, human; D044767:Ubiquitin-Protein Ligases