title: CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing.
abstract: Cullin 4B (CUL4B) is a component of the Cullin4B-Ring E3 ligase complex (CRL4B) that functions in proteolysis and is implicated in tumorigenesis. Here, we report that CRL4B is associated with histone methyltransferase SUV39H1, heterochromatin protein 1 (HP1) and DNA methyltransferases 3A (DNMT3A). We showed that CRL4B, through catalyzing H2AK119 monoubiquitination, facilitates H3K9 tri-methylation and DNA methylation, two key epigenetic modifications involved in DNA methylation-based gene silencing. Depletion of CUL4B resulted in loss of not only H2AK119 monoubiquitination but also H3K9 trimethylation and DNA methylation, leading to derepression of a collection of genes, including the tumor suppressor IGFBP3. We demonstrated that CUL4B promotes cell proliferation and invasion, which are consistent with a tumorigenic phenotype, at least partially by repressing IGFBP3. We found that the expression of CUL4B is markedly upregulated in samples of human cervical carcinoma and is negatively correlated with the expression of IGFBP3. Our experiments unveiled a coordinated action between histone ubiquitination/methylation and DNA methylation in transcription repression, providing a mechanism for CUL4B in tumorigenesis.
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.
authors.forename: R
authors.initials: R
authors.lastname: Qiu
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: H
authors.initials: H
authors.lastname: Hu
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, Canada.
authors.forename: H
authors.initials: H
authors.lastname: He
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Gong
authors.affiliation: 1] Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China [2] 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010641:Phenotype; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism
chemical_list: C517832:CUL4B protein, human; D002868:Chromosomal Proteins, Non-Histone; D044842:Cullin Proteins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D012097:Repressor Proteins; D000090266:Chromobox Protein Homolog 5; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D044767:Ubiquitin-Protein Ligases