title: Regulation of glucose metabolism by p62/SQSTM1 through HIF1α.
abstract: The signaling adaptor sequestosome 1 (SQSTM1)/p62 is frequently overexpressed in tumors and plays an important role in the regulation of tumorigenesis. Although great progress has been made, biological roles of p62 and relevant molecular mechanisms responsible for its pro-tumor activity remain largely unknown. Here, we show that p62 knockdown reduces cell growth and the expression of glycolytic genes in a manner that depends on HIF1α activity in renal cancer cells. Knockdown of p62 decreases HIF1α levels and transcriptional activity by regulating mTORC1 activity and NF-κB nuclear translocation. Furthermore, p62 interacts directly with the von Hippel-Lindau (VHL) E3 ligase complex to modulate the stability of HIF1α. Mechanistically, p62 binds to the VHL complex and competes with HIF1α. Expression of p62 inhibits the interaction of DCNL1 (also known as DCUN1D1) with CUL2 and attenuates the neddylation of CUL2, and thus downregulates the VHL E3 ligase complex activity. Functionally, HIF1α expression is required for p62-induced glucose uptake, lactate production and soft agar colony growth. Taken together, our findings demonstrate that p62 is a crucial positive regulator of HIF1α, which is a facilitating factor in p62-enhanced tumorigenesis.
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Haibing
authors.initials: H
authors.lastname: Xiao
authors.affiliation: College of Basic Medicine Science, Hubei University of Chinese Medicine, Wuhan 430065, People's Republic of China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Gan
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China xuhua@hust.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Zhangqun
authors.initials: Z
authors.lastname: Ye
mesh_terms: D044842:Cullin Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D000071456:Sequestosome-1 Protein / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D054875:Ubiquitination; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
chemical_list: C105153:CUL2 protein, human; D044842:Cullin Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D016328:NF-kappa B; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C497446:VHL protein, human; D005947:Glucose
keywords: CUL2; HIF1α; Protein stability; Transcriptional activity; p62