title: Cbx4 governs HIF-1α to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity.
abstract: Cbx4 is a polycomb group protein that is also a SUMO E3 ligase, but its potential roles in tumorigenesis remain to be explored. Here, we report that Cbx4, but not other members of the Cbx family, enhances hypoxia-induced vascular endothelial growth factor (VEGF) expression and angiogenesis in hepatocellular carcinoma (HCC) cells through enhancing HIF-1α sumoylations at K391 and K477 in its two SUMO-interacting motifs-dependent mechanisms and increasing transcriptional activity of HIF-1. The Cbx4 expression is significantly correlated with VEGF expression, angiogenesis, and the overall survival of HCC patients and also in subcutaneously and orthotopically transplanted mice HCC models. Collectively, our findings demonstrate that Cbx4 plays a critical role in tumor angiogenesis by governing HIF-1α protein.
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Chemical Biology Division of Shanghai Universities E-Institutes, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Liver Surgery, Ren-Ji Hospital, SJTU-SM, Shanghai 200021, China; Department of Pathology, Youjiang Medical College for Nationalities, Baise 533000, Guang-Xi, China.
authors.forename: Xi-Dai
authors.initials: XD
authors.lastname: Long
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Chemical Biology Division of Shanghai Universities E-Institutes, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China.
authors.forename: Hui-Ke
authors.initials: HK
authors.lastname: Jiao
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Chemical Biology Division of Shanghai Universities E-Institutes, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Mei
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Yin
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Chemical Biology Division of Shanghai Universities E-Institutes, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Ma
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Chemical Biology Division of Shanghai Universities E-Institutes, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Chemical Biology Division of Shanghai Universities E-Institutes, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Li-Shun
authors.initials: LS
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Liver Surgery, Ren-Ji Hospital, SJTU-SM, Shanghai 200021, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Liver Surgery, Ren-Ji Hospital, SJTU-SM, Shanghai 200021, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Chemical Biology Division of Shanghai Universities E-Institutes, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China. Electronic address: chengq@shsmu.edu.cn.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008025:Ligases; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025842:SUMO-1 Protein / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D063146:Polycomb-Group Proteins; D025842:SUMO-1 Protein; D042461:Vascular Endothelial Growth Factor A; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C570427:CBX4 protein, human