CUL4B ChIP-sequencing in non-treated MDA-MB-231 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE124611 | GEO | 2021/03/25
REPOSITORIES: GEO
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Project description:Here, we examined the interactions between PRMT6, poly(ADP-ribose) polymerase 1 (PARP1), and the cullin 4 B (CUL4B)-Ring E3 ligase (CRL4B) complex, to form a transcription-repressive complex that co-occupies the core clock gene PER3 promoter.
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Project description:It has been reported that PHF1, CUL4B and PRMT5 all play important roles in epigenetic regulation. We reported that PHF1, CRL4B and PRMT5 may act as a complex in transcriptional regulation and have a vital effect in breast cancer progression. So we performed ChIP-on-chip assays to find unique promoters co-targeted by PHF1, CUL4B and PRMT5. PHF1, CUL4B and PRMT5 have a predominant cooperation, at least in MDA-MB-231 cells. comparison of PHF1, CUL4B and PRMT5 target genes
2016-07-07 | E-GEOD-84071 | biostudies-arrayexpress
Project description:Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, has been reported to be overexpressed in several types of solid tumors and contributes to epigenetic silencing of tumor suppressor. However, its clinical significance and the molecular mechanisms underlying its regulation in gastric cancer (GC) remain largely unknown. Here, we showed that CUL4B was elevated in GC tissues and its overexpression was positively correlated with poor prognosis and lymph node metastasis. CUL4B knockdown in GC cells decreased proliferation, mesenchymal transition and invasion in vitro, as well as tumor growth and metastasis in nude mice, and CUL4B overexpression induced the opposite results. Further studies showed that miR-101 could inhibit CUL4B expression by directly targeting its 3’-UTR and they were inversely correlated in clinical GC specimens. Notably, a positive relationship between CUL4B and HER2 was found in GC clinical specimens, GC cells and GC xenograft tumors. Through bioinformatics analysis of miRNA-seq data and target prediction, we nominated miR-125a as a direct target of CUL4B. ChIP assays demonstrated that CUL4B directly repressed miR-125a expression by physically binding to its promoter. In addition, we confirmed miR-125a is the target of HER2. Consequently, we demonstrated that CUL4B can up-regulate HER2 expression through repressing miR-125a. Most importantly, silencing of HER2 by Herceptin or siRNA partially reversed CUL4B-induced epithelial-to-mesenchymal transition (EMT), cell invasion and metastasis in vitro and in vivo. These findings define a CUL4B-miR-125a-HER2 regulatory mechanism shed light on CUL4B oncogenic mechanisms and reveals promising therapeutic targets for progressive GC. CUL4B proteins are frequently upregulated in human cancer, yet little is known about the underlying molecular mechanisms of CUL4B induced gastric cancer(GC) carcigenesis.Here, we uncover the critical role of CUL4B in gastric cancer growth and metastasis through the regulation of HER2 expression.CUL4B contributes to GC invasion and metastasis by transcriptional repression of HER2 targeting miR-125a, which provide a new insight into how CUL4B regulates GC progression and metastasis.
2017-11-25 | GSE90501 | GEO
Project description:Cancer stem-like traits contribute to prostate cancer (PCa) progression and metastasis. Discovering and clarifying the underlying molecular mechanisms associated with PCa stem-like traits would be great beneficial to clinical treatment of advanced PCa. Cullin 4B (CUL4B) is a scaffold protein overexpressed in several solid malignancies. It is known to silence tumor suppressor through post-transcriptional manner. In this study, through gain- and loss-of-function experiments, we showed that CUL4B promotes PCa pluripotency-associated markers expression, sphere formation and anchorage-independent growth ability in virto. Mechanically, we identified BMI1 as a target of CUL4B. CUL4B unregulates BMI1 expression via epigenetically repressing microRNA-200b (miR200b) and microRNA-200c (miR200c). In addition, miR200b and miR200c (miR200b/c) could partially reverse CUL4B-induced BMI1 and pluripotency-associated marker expression. Finally, our study revealed a CUL4B-miR200b/c-BMI1 oncoprotein axis in PCa, which might give novel insight into how CUL4B promotes PCa progression through regulating cancer stem-like traits.
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2016-07-07 | GSE84071 | GEO
Project description:Cullin 4B (CUL4B) is a scaffold protein of E3 ubiquitin ligase complex and has been found frequently overexpressed in various types of cancer. By repressing tumor suppressors, CUL4B is indicated as pro-oncogenic gene in oncogenesis. Reversely, recent studies reveal that deletion of CUL4B in hematopoietic system exerts tumor suppressive effect in tumor bearing hosts. However, the role of CUL4B in tumor initiation remains unknown. Here we report that CUL4B deficiency in the intestinal epithelium accelerates ApcMin/+ tumor formation. CUL4B in cancer cells restricts the accumulation of tumor-infiltrating CD11b+Gr-1+ MDSCs to prohibit the adenoma permissive microenvironment and thus increases the number of antitumor CD8+ T cells. Addition of MDSCs to ex vivo cultured ApcMin/+; Cul4bΔIEC tumor organoids rescues their phenotypic alteration in stemness, suggesting a reciprocally strengthened immunosuppressive effect between CUL4B deficient tumor cells and MDSCs. Mechanistically, inhibiting CUL4B epigenetically activates the expression of secreted chemokines and proteins including G-CSF to enroll MDSCs. Our findings suggest that epithelial deletion of CUL4B creates a tumor-prone microenvironment during ApcMin/+ tumor formation and provide a potential strategy to overcome colon cancer initiation and progress in the Wnt-disturbed context.
2024-11-20 | GSE189382 | GEO
Project description:Background & Aims: Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions. Methods: We generated mice with intestinal epithelial-specific disruption of Cul4b (pVillin-cre; Cul4bfn/Y), inducible disruption of Cul4b (Lgr5-creERT2; Cul4bfn/Y, CAG-creERT2; Cul4bfn/Y) and their control (Cul4bfn/Y). Intestinal tissues were analyzed by histology, immunofluorescence, RNA sequencing and mass spectrum. Intestinal organoids deprived from mice with pVillin-Cre; Cul4bfn/Y, Lgr5-Cre; Cul4bfn/Y, Tg-Cul4b and their controls were used in assays to measure intestinal self-renewal, proliferation and differentiation. Wnt signaling and intestinal markers were analyzed by immunofluorescence and immunoblot assays. Differential proteins upon Cul4b ablation or Cul4b-interacting proteins were identified by mass spectrometry. Results: Cul4b specifically located at ISCs zone. Block of Cul4b impaired intestinal homeostasis maintenance by reduced self-renewal and proliferation. Transcriptome analysis revealed that Cul4b-null intestine lose ISC characterization and showed disturbed ISC niche. Mechanistically, reactivated Wnt pathway could recover intestinal dysfunction of Cul4b knockout mice. Analysis of differential total and ubiquitylated proteins uncovered the novel targeting substrate of Cullin-Ring ubiquitin ligase 4b (CRL4b), immunity-related GTPase family M member 1 (Irgm1) in intestine. Decreased Irgm1 rescued abnormally interferon signaling, overemphasized autophagy and downstream phosphate proteins in Cul4b knockout mice. Conclusion: We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
2022-08-11 | PXD021528 | Pride
Project description:A total of 619 unique promoters were found to be co-targeted by CUL4B and EZH2, among which only 53 were overlapped with the 891 targets of BMI EZH2/PRC2 and CUL4B/CRL4B have a predominant cooperation, at least in KYSE410 cells.
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Project description:Peroxisome proliferator–activated receptor γ (PPARγ) is the central regulator of adipogenesis, and its dysregulation is linked to obesity and metabolic diseases. Identification of the factors that regulate PPARγ expression and activity is therefore crucial for combating obesity. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor with a known role in xenobiotic detoxification. Recent studies have suggested that AhR also plays essential roles in energy metabolism. However, the detailed mechanisms remain unclear. We previously reported that experiments with adipocyte-specific Cullin 4b (Cul4b)-knockout mice showed that CUL4B suppresses adipogenesis by targeting PPARγ. Here, using immunoprecipitation, ubiquitination, real-time PCR and Gst-pulldown assays, we report that AhR functions as the substrate receptor in CUL4B–RING E3 ubiquitin ligase (CRL4B) complex and is required for recruiting PPARγ. AhR overexpression reduced PPARγ stability and suppressed adipocyte differentiation, and AhR knockdown stimulated adipocyte differentiation in 3T3-L1 cells. Furthermore, we found that two lysine sites on residues 268 and 293 in PPARγ are targeted for CRL4B-mediated ubiquitination, indicating cross-talk between acetylation and ubiquitination. Our findings establish a critical role of AhR in regulating PPARγ stability and suggest that the AhR–PPARγ interaction may represent a potential therapeutic target for managing metabolic diseases arising from PPARγ dysfunction.
2019-11-01 | PXD015830 | Pride
Project description:Hierarchical organization of intestine relies on their stem cells by self-renew and producing committed progenitors. Although signals like Wnt are known to animate the continued renewal by maintaining intestinal stem cells (ISCs) activity, molecular mechanisms especially E3 ubiquitin ligases that modulate ISCs ‘stemness’ and supportive niche have not been well understood. Here, we investigated the role of Cullin 4B (Cul4b) in regulating ISC functions.We conclude that Cul4b is essential for ISC self-renewal and Paneth cell function by targeting Irgm1 and modulating Wnt signaling. Our results demonstrate that Cul4b is a novel ISC stemness and niche regulator.
2022-06-17 | GSE157818 | GEO