Cbx4 governs HIF-1α to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity

Jie Li; Ying Xu; Xi-Dai Long; Wei Wang; Hui-Ke Jiao; Zhu Mei; Qian-Qian Yin; Li-Na Ma; Ai-Wu Zhou; Li-Shun Wang; Ming Yao; Qiang Xia; Guo-Qiang Chen

doi:10.1016/j.ccr.2013.12.008

Cbx4 governs HIF-1α to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity

Cancer Cell. 2014 Jan 13;25(1):118-31. doi: 10.1016/j.ccr.2013.12.008.

Authors

Jie Li¹, Ying Xu², Xi-Dai Long³, Wei Wang¹, Hui-Ke Jiao², Zhu Mei¹, Qian-Qian Yin², Li-Na Ma¹, Ai-Wu Zhou¹, Li-Shun Wang¹, Ming Yao⁴, Qiang Xia⁴, Guo-Qiang Chen⁵

Affiliations

¹ 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.
² Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China.
³ 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.
⁴ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Liver Surgery, Ren-Ji Hospital, SJTU-SM, Shanghai 200021, China.
⁵ 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: [email protected].

PMID: 24434214
DOI: 10.1016/j.ccr.2013.12.008

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Carcinoma, Hepatocellular / blood supply
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology
Chromatin Immunoprecipitation
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation, Neoplastic / physiology
Heterografts
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Immunohistochemistry
Ligases
Liver Neoplasms / blood supply
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology
Mice
Neovascularization, Pathologic / metabolism*
Polycomb-Group Proteins / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
SUMO-1 Protein / metabolism
Ubiquitin-Protein Ligases / metabolism*
Vascular Endothelial Growth Factor A / biosynthesis

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Polycomb-Group Proteins
SUMO-1 Protein
Vascular Endothelial Growth Factor A
Ubiquitin-Protein Ligases
Ligases
CBX4 protein, human