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CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing

Oncogene volume 34, pages 104–118 (2015)Cite this article

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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.

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Acknowledgements

This work was supported by grants (81322032, 31171240 and 90919053 to YW) from the National Natural Science Foundation of China, grant (NECT-12–1067 to YW) from the Ministry of Education of China, and grant (2013CB910900 to YG) from the National Basic Research Program of China.

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  1. Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong, China

    Y Yang, R Liu, H Hu, Q Ji, Y Gong & Y Wang

  2. Department of Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin, China

    R Qiu, Y Zheng, W Huang, Y Shang & Y Wang

  3. Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, Canada

    H He

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Yang, Y., Liu, R., Qiu, R. et al. CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing. Oncogene 34, 104–118 (2015). https://doi.org/10.1038/onc.2013.522

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