Knockdown of CTCF reduces the binding of EZH2 and affects the methylation of the SOCS3 promoter in hepatocellular carcinoma

Wei, Ling; Liu, Qiuying; Huang, Yuan; Liu, Zhong‐Jian; Zhao, Rongzhen; Li, Bo; Zhang, Jing; Sun, Chengjun; Gao, Bo; Ding, Xueqin; Yu, Xiaoqin; He, Jingjing; Sun, Aimin; Qin, Yang

doi:10.1016/j.biocel.2020.105685

Cited by 13 publications

(11 citation statements)

References 45 publications

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“…Since sites of compromised CTCF binding are generally not proximal to sites of gained H3K27ac or H3K4me3, it is unlikely that the loss of CTCF drives the gain of activating marks through direct mechanisms. For example, it is unlikely that compromised CTCF binding would lead to the loss of recruitment of antagonistic epigenetic writers, such as EZH2 77 at sites many kilobases away where H3K27ac is subsequently accumulated. Therefore, we can infer that the reshuffling of subTADs is driving the redistribution of H3K27ac and H3K4me3 more so than altered CTCF itself, by allowing novel chromatin contacts between genomic regions.…”

Section: Discussionmentioning

confidence: 99%

3D chromatin remodeling potentiates transcriptional programs driving cell invasion

Lebeau

Jangal

Zhao

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The contribution of deregulated chromatin architecture, including topologically associated domains (TADs), to cancer progression remains ambiguous. CCCTC-binding factor (CTCF) is a central regulator of higher-order chromatin structure that undergoes copy number loss in over half of all breast cancers, but the impact of this defect on epigenetic programming and chromatin architecture remains unclear. We find that under physiological conditions, CTCF organizes subTADs to limit the expression of oncogenic pathways, including phosphatidylinositol 3-kinase (PI3K) and cell adhesion networks. Loss of a single CTCF allele potentiates cell invasion through compromised chromatin insulation and a reorganization of chromatin architecture and histone programming that facilitates de novo promoter-enhancer contacts. However, this change in the higher-order chromatin landscape leads to a vulnerability to inhibitors of mTOR. These data support a model whereby subTAD reorganization drives both modification of histones at de novo enhancer-promoter contacts and transcriptional up-regulation of oncogenic transcriptional networks.

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Section: Discussionmentioning

confidence: 99%

3D chromatin remodeling potentiates transcriptional programs driving cell invasion

Lebeau

Jangal

Zhao

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Indeed, knockdown of CTCF in hepatocellular carcinoma causes loss of CTCF and EZH2 binding, decreased H3K27me3 marks and DNA hypomethylation at SOCS3 promoter. CTCF depletion led to SOCS3 upregulation which confirms the role of CTCF in gene silencing through recruitment of PcG subunits (Wei, Liu et al 2020). In line with this, ASXL1 is important for normal haematopoiesis (Abdel-Wahab, Gao et al 2013) through interaction with cohesin and stabilization of RAD21 and SMC1A subunits, mainly in promoter regions.…”

Section: Chromatin Remodeling Proteins and Ctcfmentioning

confidence: 52%

AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding

Mujahed

Miliara

Neddermeyer

et al. 2020

Blood

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CCTC-binding factor (CTCF) is a key regulator of gene expression through organization of the chromatin structure. Still, it is unclear how CTCF binding is perturbed in leukemia or in cancer in general. We studied CTCF binding by chromatin immunoprecipitation sequencing in cells from patients with acute myeloid leukemia (AML) and in normal bone marrow (NBM) in the context of gene expression, DNA methylation, and azacitidine exposure. CTCF binding was increased in AML compared with NBM. Aberrant CTCF binding was enriched for motifs for key myeloid transcription factors such as CEBPA, PU.1, and RUNX1. AML with TET2 mutations was characterized by a particularly strong gain of CTCF binding, highly enriched for gain in promoter regions, while AML in general was enriched for changes at enhancers. There was a strong anticorrelation between CTCF binding and DNA methylation. Gain of CTCF occupancy was associated with increased gene expression; however, the genomic location (promoter vs distal regions) and enrichment of motifs (for repressing vs activating cofactors) were decisive for the gene expression pattern. Knockdown of CTCF in K562 cells caused loss of CTCF binding and transcriptional repression of genes with changed CTCF binding in AML, as well as loss of RUNX1 binding at RUNX1/CTCF-binding sites. In addition, CTCF knockdown caused increased differentiation. Azacitidine exposure caused major changes in CTCF occupancy in AML patient cells, partly by restoring a CTCF-binding pattern similar to NBM. We conclude that AML displays an aberrant increase in CTCF occupancy that targets key genes for AML development and impacts gene expression.

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“…It was previously found that the expression of SOCS3 in hepatocellular carcinoma tissues and cell lines was negatively correlated with EZH2 and depended on its promoter methylation status through TCGA hepatocellular carcinoma data analysis. The promoter recruitment of SOCS3 gene by CTCF dependent EZH2 may be involved in the epigenetic silencing of SOCS3 and the regulation of its gene expression (13). It was shown in in vivo and in vitro experiments of a previous study, upregulated GAS5 promoted the expression of SOCS3, thus inhibiting the growth, metastasis, and Gem resistance of pancreatic cancer (14).…”

Section: Discussionmentioning

confidence: 89%

“…Moreover, lncRNA UCA1 is physically linked to the enhancer of zeste homolog 2 (EZH2), which inhibits p27Kip1 through histone methylation (H3K27me3) in p27Kip1 promoter, thus promoting tumorigenesis in nude mice in hepatocellular carcinoma (12). In addition, CTCF dependent recruitment of EZH2 to the SOCS3 gene promoter is likely to participate in the epigenetic silencing of SOCS3 and in regulating its gene expression in cancer development (13). SOCS3 overexpression has been observed to suppress malignant behaviors and Gem resistance of pancreatic cancer cells (14).…”

Section: Introductionmentioning

confidence: 99%

Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis

Chi

Liu

2021

Front. Oncol.

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ObjectivePancreatic cancer is associated with poor prognosis and dismal survival rates. This study aims to investigate roles of lncRNA UCA1-loaded exosomes secreted by pancreatic stellate cells (PSCs) in Gemcitabine (Gem) resistance of pancreatic cancer under hypoxia, which involves the methylation of SOCS3 and EZH2 recruitment.MethodsThe exosomes were isolated from PSCs and hypoxic PSCs (HPSCs), and co-cultured with pancreatic cancer cells transduced with manipulated lncRNA UCA1, EZH2, and SOCS3. The interaction among lncRNA UCA1, EZH2, and SOCS3 was characterized by RIP and ChIP assays. Next, MTT assay, flow cytometry and TUNEL staining and Transwell assay were used to detect cell viability, apoptosis, invasion, and migration. Gem-resistant pancreatic cancer cell line (GemMIA-R3) was established, which was applied in a mouse xenograft model of pancreatic cancer, with MTT assay to determine Gem sensitivity.ResultsLncRNA UCA1 was highly expressed, while SOCS3 was poorly expressed in pancreatic cancer tissues. Hypoxia induced activation of PSCs and promoted release of exosomes. LncRNA UCA1 delivered by hypoxic PSC-derived exosomes (HPSC-EXO) regulated histone methylation level in SOCS3 gene region through recruitment of EZH2. In vitro and in vivo experimental results confirmed that lncRNA UCA1-loaded HPSC-EXO promoted malignant phenotypes, inhibited apoptosis, and promoted Gem resistance of pancreatic cancer cells as well as tumorigenesis in mice.ConclusionUnder hypoxic conditions, exosomes secreted by hypoxia-induced PSCs deliver lncRNA UCA1 into pancreatic cancer cells, where lncRNA UCA1 recruits EZH2 and regulates histone methylation level in SOCS3 gene region, thereby augmenting pancreatic cancer resistance to Gem.

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Knockdown of CTCF reduces the binding of EZH2 and affects the methylation of the SOCS3 promoter in hepatocellular carcinoma

Cited by 13 publications

References 45 publications

3D chromatin remodeling potentiates transcriptional programs driving cell invasion

3D chromatin remodeling potentiates transcriptional programs driving cell invasion

AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding

Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis

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