title: CUL4B activates Wnt/β-catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists.
abstract: Activation of Wnt/β-catenin signalling is frequently observed in many types of cancer including hepatocellular carcinoma (HCC). We recently reported that cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, is overexpressed in many types of solid tumours and contributes to epigenetic silencing of tumour suppressors. In this study, we characterized the function of CUL4B in HCC and investigated whether CUL4B is involved in the regulation of Wnt/β-catenin signalling. CUL4B and β-catenin were frequently up-regulated and positively correlated in HCC tissues. CUL4B activated Wnt/β-catenin signalling by protecting β-catenin from GSK3-mediated degradation, achieved through CUL4B-mediated epigenetic silencing of Wnt pathway antagonists. Knockdown of CUL4B resulted in the up-regulation of Wnt signal antagonists such as DKK1 and PPP2R2B. Simultaneous knockdown of PPP2R2B partially reversed the down-regulation of β-catenin signalling caused by CUL4B depletion. Furthermore, CRL4B promoted the recruitment and/or retention of PRC2 at the promoters of Wnt antagonists and CUL4B knockdown decreased the retention of PRC2 components as well as H3K27me3. Knockdown of CUL4B reduced the proliferation, colony formation, and invasiveness of HCC cells in vitro and inhibited tumour growth in vivo, and these effects were attenuated by introduction of exogenous β-catenin or simultaneous knockdown of PPP2R2B. Conversely, ectopic expression of CUL4B enhanced the proliferation and invasiveness of HCC cells. We conclude that CUL4B can up-regulate Wnt/β-catenin signalling in human HCC through transcriptionally repressing Wnt antagonists and thus contributes to the malignancy of HCC.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, 250012, China.
authors.forename: Jupeng
authors.initials: J
authors.lastname: Yuan
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qian
authors.forename: Zhaojian
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wei
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Liang
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C517832:CUL4B protein, human; D044842:Cullin Proteins; D009419:Nerve Tissue Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; C505936:PPP2R2B protein, human; D054648:Protein Phosphatase 2
keywords: CUL4B; HCC; PRC2; Wnt antagonist; epigenetic regulation; β-catenin