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

Yang, Yajuan; Liu, R; Qiu, Rongfang; Zheng, Yu; Huang, Wei; Hu, Hailong; Ji, Qinghong; He, Hongbin; Shang, Yongfeng; Gong, Yaoqin; Wang, Y

doi:10.1038/onc.2013.522

Cited by 94 publications

(98 citation statements)

References 83 publications

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“…Immunoprecipitation assays were performed as described previously (Hu et al, 2012;Yang et al, 2013). Briefly, 1610 7 cells were collected, washed with cold PBS and then lysed with lysis buffer at 4˚C for 30 min.…”

Section: Immunoprecipitation and Gst Pulldownmentioning

confidence: 99%

“…CUL4B ablation could block the degradation of WDR5, a core subunit of the histone H3 lysine 4 (H3K4) methyltransferase complex, and thus increase H3K4 trimethylation (H3K4me3) on some neuronal gene promoters, leading to their upregulation (Nakagawa and Xiong, 2011). Recently, we have shown that CRL4B functions as a transcriptional co-repressor of tumor suppressors by monoubiquitylating H2AK119 and coordinating with either the PRC2 complex or with DNA methyltransferase, HP1 and SUV39H1 to regulate histone methylation or DNA methylation (Hu et al, 2012;Yang et al, 2013). Here, we show that CUL4B depletion can inhibit cell proliferation owing to the upregulation of Cdkn1a and Cdkn1c.…”

Section: Introductionmentioning

confidence: 99%

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CRL4B interacts and coordinates with SIN3A/HDAC complex to repress CDKN1A in driving cell cycle progression

Yang

et al. 2014

Journal of Cell Science

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CUL4B, a scaffold protein that assembles the CRL4B ubiquitin ligase complex, participates in the regulation of a broad spectrum of biological processes. Here, we demonstrate a crucial role of CUL4B in driving cell cycle progression. We show that loss of CUL4B results in a significant reduction in cell proliferation and causes G1 cell cycle arrest, accompanied by the upregulation of the cyclindependent kinase (CDK) inhibitors (CKIs) p21 and p57 (encoded by CDKN1A and CDKN1C, respectively). Strikingly, CUL4B was found to negatively regulate the function of p21 through transcriptional repression, but not through proteolysis. Furthermore, we demonstrate that CRL4B and SIN3A-HDAC complexes interact with each other and co-occupy the CDKN1A and CDKN1C promoters. Lack of CUL4B led to a decreased retention of SIN3A-HDAC components and increased levels of acetylated H3 and H4. Interestingly, the ubiquitylation function of CRL4B is not required for the stable retention of SIN3A-HDAC on the promoters of target genes. Thus, in addition to directly contributing to epigenetic silencing by catalyzing H2AK119 monoubiquitylation, CRL4B also facilitates the deacetylation function of SIN3A-HDAC. Our findings reveal a coordinated action between CRL4B and SIN3A-HDAC complexes in transcriptional repression.

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Section: Immunoprecipitation and Gst Pulldownmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CRL4B interacts and coordinates with SIN3A/HDAC complex to repress CDKN1A in driving cell cycle progression

Yang

et al. 2014

Journal of Cell Science

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“…Unlike CUL4A and other cullins, CUL4B harbors an N-terminal nuclear localization sequence that directs it to nucleus to regulate cell functions in an epigenetic manner (18,(25)(26)(27). Recently, we have shown that cullin 4B-RING E3 ligase (CRL4B) functions as a transcriptional corepressor by catalyzing H2AK119 ubiquitination (H2A119ub1) and coordinating with polycomb repressive complex 2 (PRC2) to regulate histone H3 lysine 27 (H3K27) trimethylation (28,29). Other studies have demonSomatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion.…”

Section: Introductionmentioning

confidence: 99%

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

Cui

Yang

et al. 2017

Journal of Clinical Investigation

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Figure 1. CUL4B deficiency in pancreatic δ cells impairs glucose metabolism. (A and B)Western blots and quantitative data for CUL4A and CUL4B protein levels in islets from 12-week-old diabetic db/db mice and their heterozygous littermates (db/+). n = 6 mice per group. Representative Western blots from at least 3 independent experiments are shown. (C) Immunostaining for CUL4B (green) and somatostatin (SST, red) in pancreatic sections from db/db and db/+ mice. Scale bar: 100 μm. n = 6 mice per group; 4-7 random areas were selected from each islet section, and 10 sections were randomly selected from each mouse. Insulininduced decreases in blood glucose levels were significantly lower in Sst-Cre +/-Cul4b fl/Y mice than in their WT littermates, and they did not return to baseline levels at the 2-hour time point, whereas the levels of their WT littermates did (n = 9-11). *P < 0.05; **P < 0.01; ***P < 0.001. db/db mice were compared with their db/+ littermates, and Sst-Cre +/-Cul4b fl/Y mice were compared with their WT littermates. Error bars in F represent mean ± SD; other bars represent mean ± SEM. All data were analyzed using 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 6 3 3 jci.orgVolume 127 Number 7 July 2017mental Figure 1E). Immunofluorescence also showed no significant differences in islet or β or δ cell numbers between +/-mice, the knockout mice exhibited increased glucose levels after 2 hours of feeding following a 16-hour fast ( Figure 1G). Accordingly, during a glucose tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice were 33% and 30% higher at 30 minutes and 120 minutes, respectively, than those of the control group consisting of both Sst-Cre +/-and Cul4b fl/Y mice ( Figure 1H). In addition, during the insulin tolerance test, the blood glucose levels of Sst-Cre +/-Cul4b fl/Y mice unexpectedly decreased more dramatically and rapidly than those of the Sst-Cre +/-control mice in response to insulin stimulation ( Figure 1I). Insulin and somatostatin content as well as kidney, brain, heart, liver, and stomach weights were not found to be significantly different between the mice was 140% and 40% higher than that of Sst-Cre +/-mice at 5 minutes and 60 minutes, respectively ( Figure 2H). In contrast to the results found for the Sst-Cre +/-Cul4b fl/Y mice, CUL4B defistrated that CRL4 ubiquitinates WD repeat-containing protein 5 (WDR5), a core subunit of H3K4 methyltransferase complexes, for degradation in the nucleus, thereby promoting increased H3K4 methylation levels (30). However, whether CUL4B or its E3 ligase complex CRL4B-PRC2 participates in the functioning or development of Langerhans islets has not been studied. In this study, we found that CUL4B expression levels are decreased in db/db mice. Therefore, we crossed mice expressing Cre under the insulin II promotor (Ins2-Cre) and mice expressing Cre under the somatostatin promoter (Sst-Cre) with Cul4b fl/fl mice to characterize CUL4B functions in specific cell types of the islet circuit. Although In...

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“…CUL4B has recently been shown to be highly expressed in a variety of human malignancy and is positively correlated with tumor progression (25,26,29,39,40). In the current study, we demonstrated that CUL4B functions to limit the expansion and activity of MDSCs that are an integral part of the immunosuppressive tumor microenvironment.…”

Section: Discussionmentioning

confidence: 57%

“…Recently, CUL4B has been shown to be substantially upregulated in various types of solid tumors and possess potent oncogenic properties. H2AK119 monoubiquitination catalyzed by CRL4B is critical for epigenetic inactivation of tumor suppressors by PRC2, SUV39H1/HP1/DNMT and SIN3A/histone deacetylase (HDAC) complexes (25)(26)(27). In this study, we demonstrated that CUL4B, AKT and b-catenin function in an axis that negatively regulates MDSCs.…”

Section: Introductionmentioning

confidence: 71%

The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment

Qian

Yuan

et al. 2015

Cancer Research

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Cancer progression requires a permissive microenvironment that shields cancer from the host immunosurveillance. The presence of myeloid-derived suppressor cells (MDSC) is a key feature of a tumor-permissive microenvironment. Cullin 4B (CUL4B), a scaffold protein in the Cullin 4B-RING E3 ligase complex (CRL4B), represses tumor suppressors through diverse epigenetic mechanisms and is overexpressed in many malignancies. We report here that CUL4B unexpectedly functions as a negative regulator of MDSC functions in multiple tumor settings. Conditional ablation of CUL4B in the hematopoietic system, driven by Tek-Cre, resulted in significantly enhanced accumulation and activity of MDSCs. Mechanistically, we demonstrate that the aberrant abundance of MDSCs in the absence of CUL4B was mediated by the downregulation of the AKT/b-catenin pathway. Moreover, CUL4B repressed the phosphatases PP2A and PHLPP1/2 that dephosphorylate and inactivate AKT to sustain pathway activation. Importantly, the CUL4B/AKT/b-catenin axis was downregulated in MDSCs of healthy individuals and was further suppressed in tumor-bearing mice and cancer patients. Thus, our findings point to a proand antitumorigenic role for CUL4B in malignancy, in which its ability to impede the formation of a tumor-supportive microenvironment may be context-specific. Cancer Res; 75(23); 5070-83.Ó2015 AACR.

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

Cited by 94 publications

References 83 publications

CRL4B interacts and coordinates with SIN3A/HDAC complex to repress CDKN1A in driving cell cycle progression

CRL4B interacts and coordinates with SIN3A/HDAC complex to repress CDKN1A in driving cell cycle progression

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions

The CUL4B/AKT/β-Catenin Axis Restricts the Accumulation of Myeloid-Derived Suppressor Cells to Prohibit the Establishment of a Tumor-Permissive Microenvironment

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