An Artificial CTCF Peptide Triggers Efficient Therapeutic Efficacy in Ocular Melanoma

Wen, Xuyang; Wang, Huixue; Chai, Peiwei; Fan, Jiayan; Zhang, Xiaoyu; Ding, Tianyi; Jia, Renbing; Ge, Shengfang; Zhang, He; Fan, Xianqun

doi:10.1016/j.omto.2020.07.004

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…41 Furthermore, SPARC deletion in transgenic adenocarcinoma of mouse prostate (TRAMP) mice led to enhanced development and progression of cancer. 42 In addition, our data demonstrate upregulation of ITGA4, MMP12, and SELL, three proteins involved in cell invasion and tumorigenesis, [43][44][45] all of which could lead to increased motility of CHD1 KO cells.…”

Section: Discussionmentioning

confidence: 64%

The role of chromodomain helicase DNA binding protein 1 (CHD1) in promoting an invasive prostate cancer phenotype

Kareddula

Medina

Petrosky

et al. 2021

Therapeutic Advances in Urology

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Background: Prostate cancer (PCa) phenotypes vary from indolent to aggressive. Molecular subtyping may be useful in predicting aggressive cancers and directing therapy. One such subtype involving deletions of chromodomain helicase DNA binding protein 1 ( CHD1), a tumor suppressor gene, are found in 10–26% of PCa tumors. In this study, we evaluate the functional cellular effects that follow CHD1 deletion. Methods: CHD1 was knocked out (KO) in the non-tumorigenic, human papillomavirus 16 (HPV16)-immortalized prostate epithelial cell line, RWPE-1, using CRISPR/Cas9. In vitro assays such as T7 endonuclease assay, western blot, and sequencing were undertaken to characterize the CHD1 KO clones. Morphologic and functional assays for cell adhesion and viability were performed. To study expression of extracellular matrix (ECM) and adhesion molecules, a real-time (RT) profiler assay was performed using RWPE-1 parental, non-target cells (NT2) and CHD1 KO cells. Result: Compared to parental RWPE-1 and non-target cells (NT2), the CHD1 KO cells had a smaller, rounder morphology and were less adherent under routine culture conditions. Compared to parental cells, CHD1 KO cells showed a reduction in ECM and adhesion molecules as well as a greater proportion of viable suspension cells when cultured on standard tissue culture plates and on plates coated with laminin, fibronectin or collagen I. CHD1 KO cells showed a decrease in the expression of secreted protein acidic and rich in cysteine (SPARC), matrix metalloproteinase 2 (MMP2), integrin subunit alpha 2 (ITGA2), integrin subunit alpha 5 (ITGA5), integrin subunit alpha 6 (ITGA6), fibronectin (FN1), laminin subunit beta-3 precursor (LAMB3), collagen, tenascin and vitronectin as compared to parental and NT2 cells. Conclusion: These data suggest that in erythroblast transformation specific (ETS) fusion-negative, phosphatase and tensin homolog ( PTEN) wildtype PCa, deletion of CHD1 alters cell-cell and cell-matrix adhesion dynamics, suggesting an important role for CHD1 in the development and progression of PCa.

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Section: Discussionmentioning

confidence: 64%

The role of chromodomain helicase DNA binding protein 1 (CHD1) in promoting an invasive prostate cancer phenotype

Kareddula

Medina

Petrosky

et al. 2021

Therapeutic Advances in Urology

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“…CTCF has been discovered to recruit histone modifiers, which regulates gene expression through alteration of the chromatin structure 46–48 . Our previous data indicated that knockdown of CTCF mainly affected histone acetylation rather than histone methylation of the promoter region of PTGS2 (Figure S13A–C), suggesting that CTCF most likely recruited histone acetyltransferase (HAT) to the promoter region of PTGS2.…”

Section: Resultsmentioning

confidence: 98%

The CTCF/LncRNA‐PACERR complex recruits E1A binding protein p300 to induce pro‐tumour macrophages in pancreatic ductal adenocarcinoma via directly regulating PTGS2 expression

Liu

Wang

Zhu

et al. 2022

Clinical & Translational Med

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Background Tumour‐associated macrophages (TAMs) play an important role in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to study the epigenetic mechanisms in regulating pro‐tumour M2‐polarised TAMs in the PDAC tumour microenvironment. Methods This study was conducted based on ex vivo TAMs isolated from PDAC tissues and in vitro THP1‐derived TAM model. RNA‐sequencing (RNA‐seq), assay for transposase‐accessible chromatin with sequencing and chromatin immunoprecipitation sequencing were performed to investigate gene expression, chromatin accessibility, transcription factor binding sites and histone modifications. Gene knockdown in THP1‐derived TAMs was performed with lentivirus, and the impact of THP1‐derived TAMs on invasion and metastasis ability of PDAC cells were investigated with in vitro and in vivo functional assays. RNA‐chromatin interaction was analysed by chromatin isolation through RNA purification with sequencing. RNA‐protein interaction was studied by RNA immunoprecipitation and RNA pull‐down. Results Our data showed that the transcription factor CTCF (CCCTC‐binding factor) was highly expressed in TAMs and predicted to be significantly enriched in hyper‐accessible chromatin regions when compared to monocytes. High infiltration of CTCF+ TAMs was significantly associated with poor prognosis in PDAC patients. Knockdown of CTCF in THP1‐derived TAMs led to the down‐regulation of specific markers for M2‐polarised TAMs, including CD206 and CD163. When THP1‐derived TAMs with CTCF knockdown, they showed a decreased ability of invasion and metastasis. Further integrative analysis of multi‐omics data revealed that prostaglandin‐endoperoxide synthase 2 (PTGS2) and PTGS2 antisense NF‐κB1 complex‐mediated expression regulator RNA (PACERR) were critical downstream targets of CTCF and positively correlated with each other, which are closely situated on a chromosome. Knockdown of PACERR exhibited a similar phenotype as observed in CTCF knockdown THP1‐derived TAMs. Moreover, PACERR could directly bind to CTCF and recruit histone acetyltransferase E1A binding protein p300 to the promoter regions of PACERR and PTGS2, thereby enhancing histone acetylation and gene transcription, promoting the M2 polarization of TAMs in PDAC. Conclusions Our study demonstrated a novel epigenetic regulation mechanism of promoting pro‐tumour M2‐polarised TAMs in the PDAC tumour microenvironment.

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“…CTCF involvement in cell migration is ambiguous; on one hand it was shown to repress breast cancer cell migration and invasion 35,36 , while on the other hand it was shown to support migration and/or invasion of various primary and cancerous cells including human corneal epithelial cells 37,38 , cortical neurons 39 , skin-resident dendritic cells 40 , prostate cancer cells 41,42 , ovarian cancer cells 43 , gastric cancer cells 44 and melanoma cells 45 . Although it is assumed that CTCF affects cell migration by its ability to regulate transcription, the exact mechanism by which CTCF controls transcription to control cell migration has not been determined yet.…”

Section: Introductionmentioning

confidence: 99%

The CTCF-H3K27me3 axis supports melanoma cell migration by repressing cholesterol biosynthesis

Kaczmarczyk

Levi

Salmon‐Divon

et al. 2023

Preprint

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CCCTC-binding factor (CTCF) is a zinc finger protein that regulates correct three-dimensional chromatin folding in addition to activation and repression of transcription and splicing. CTCF was found to affect tumor cell migration, however the molecular mechanism is still obscure. To identify the molecular mechanism by which CTCF supports melanoma cell migration we used mouse melanoma cells with a partial loss of function (pLoF) of CTCF generated by the CRISPR-Cas9 system. Here we show that CTCF pLoF inhibited cell migration rate. Using RNA sequencing we identified an increase in the expression of multiple enzymes in the cholesterol biosynthesis pathway along with an increase in the cellular cholesterol levels. Inhibition of cholesterol synthesis in CTCF pLoF cells by Fatostatin restored the cellular migration rate, suggesting that CTCF supports cell migration by inhibition of cholesterol synthesis. Detailed analysis of the promoter of Hmgcs1, an upstream enzyme in the cholesterol synthesis pathway, revealed that CTCF pLoF led to reduced H3K27me3 levels in parallel to increased binding of the transcriptional activator SREBP2. Moreover, inhibition of H3K27 methylation in wildtype cells led to increased SREBP2 binding to this promoter. Taken together, our results suggest that CTCF represses transcription of Hmgc1 by promoting H3K27 methylation to suppress SREBP2 binding. By that, CTCF fine tune the cellular cholesterol levels to support cell migration.

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An Artificial CTCF Peptide Triggers Efficient Therapeutic Efficacy in Ocular Melanoma

Cited by 4 publications

References 37 publications

The role of chromodomain helicase DNA binding protein 1 (CHD1) in promoting an invasive prostate cancer phenotype

The role of chromodomain helicase DNA binding protein 1 (CHD1) in promoting an invasive prostate cancer phenotype

The CTCF/LncRNA‐PACERR complex recruits E1A binding protein p300 to induce pro‐tumour macrophages in pancreatic ductal adenocarcinoma via directly regulating PTGS2 expression

The CTCF-H3K27me3 axis supports melanoma cell migration by repressing cholesterol biosynthesis

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