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C1Q + TPP1 + macrophages promote colon cancer progression through SETD8-driven p53 methylation.

ABSTRACT: In many tumors, the tumor suppressor TP53 (p53) is not mutated, but experiences functional inactivation. Notwithstanding, restoring p53 function emerges as an appealing therapeutic approach for tumors exhibiting wild-type p53 (p53WT). However, the mechanisms underlying the functional inactivation of p53 in these tumors remain poorly understood. Previously, we identified SETD8 as a critical suppressor of p53 activity in neuroblastomas. SETD8 is the sole known enzyme that mono-methylates p53 on lysine 382 (p53K382me1), resulting in the inhibition of its pro-apoptotic and growth-arresting functions. In this study, we observed high expression levels of SETD8 and p53K382me1 in 185 colorectal cancer (CRC) tissue samples, being negatively associated with patient survival probability. Significantly, the expression of p53K382me1 resulted confined to colorectal cancer stem cells and tumor-associated macrophages (TAM) in tissues obtained from CRC patients. Within CRC patient cohorts, high expression of p53K382me1 levels in both stem and immune cells predict decreased survival probability. The SETD8-mediated inactivation of p53 through p53K382me1 may serve as an early requirement for tumor initiation, particularly in inflammation-induced cancers, and as a functional biomarker and therapeutic target in advanced CRCs

ORGANISM(S): Homo sapiens

PROVIDER: GSE262144 | GEO | 2025/04/03

REPOSITORIES: GEO

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Development of novel chemical inhibitors of SETD8

Project description:SETD8 is a histone methyltransferase that catalyzes the monomethylation of histone H4K20. Overexpressed in cancer, several studies have suggested that it could be a potential target for treatment in certain tumors. However, there are currently very few SETD8 inhibitors, and all of them have bad pharmacological properties. Based on previously published structures of SETD8 bound to an H4K20me peptide, we have discovered a new chemical series of SETD8 inhibitors. As part of the characterization of these molecules, we conducted Thermal Proteome Profiling, aiming to discover potential additional targets as well as a better understanding of the signaling pathways that are affected by the drug.

2024-10-17 | PXD051199 | Pride

Epigenetic siRNA and chemical screens identify SETD8 inhibition as a new therapeutic strategy of p53 reactivation in high-risk Neuroblastoma.

Project description:Purpose: The intergration of genetic and chemical screens identified SETD8 as a new druggable target in neuroblastoma tumor. The goal of this study is to evaluate the transcriptome profiling (RNA-seq) of Neuroblastoma cell lines after genetic and pharmacological inhibition of SETD8. Methods: mRNA profiles of NB cells after genetic and pharmacological inhibition of SETD8 were generated by deep sequencing in duplicate with Ilumina HiSeq2500 using Illumina TruSeq V4. The sequence reads were analyzed with software Trimmomatic, STAR and edgeR to determine the differetially expressed genes. qRT–PCR validation was performed using SYBR Green assays. Results: About 60 million sequence reads per sample were mapped to the human genome (hg19). Approximately 10% of the transcripts showed differential expression between the control and the treated samples, with a fold change ≥1.5 and p value <0.05. Altered expression of 12 genes was confirmed with qRT–PCR, demonstrating the high degree of sensitivity of the RNA-seq method. Hierarchical clustering of differentially expressed genes uncovered several as yet uncharacterized genes that may contribute to SETD8 function. Conclusions: Our study identifies SETD8 as a new therapeutic target in Neuroblastoma tumor. RNA-seq transcriptome analyses and functional studies revealed that SETD8 ablation rescued the proapoptotic and cell-cycle arrest functions of p53 through reactivation of the p53 canonical pathway by decreasing p53k382me1.

2017-01-09 | GSE81626 | GEO

The histone methyltransferase Setd8 represses Gata2 expression and regulates erythroid maturation

Project description:The chromatin modifying enzymes that drive the erythroid-specific transcription program are incompletely understood. Setd8 is the sole histone methyltransferase in mammals capable of generating mono-methylated histone H4 lysine 20 (H4K20me1) and is expressed at significantly higher levels in erythroid cells than any other cell- or tissue- type, suggesting that Setd8 has an erythroid-specific function. To test this hypothesis, stable knockdown of Setd8 was established in extensively self-renewing erythroblasts (ESREs), a well-characterized, non-transformed, model of erythroid maturation. Setd8 knockdown impaired erythroid maturation, characterized by a delay in hemoglobin accumulation, larger cell area, persistent kit expression, incomplete nuclear condensation, and lower rates of enucleation than control cells. Setd8 knockdown did not alter ESRE proliferation or viability, or result in accumulation of DNA damage. Global gene expression analyses following Setd8 knockdown suggests that in erythroid cells, Setd8 functions primarily as a repressor and demonstrated high levels of Gata2 expression. Setd8 occupies critical regulatory elements in the Gata2 locus, and knockdown of Setd8 resulted in loss of H4K20me1 and gain of H4 acetylation at the Gata2 1S promoter. Taken together, these results imply that Setd8 is an important regulator of erythroid maturation that works in part through repression of Gata2. RNA-seq was performed of Setd8 knockdown and control cells, both while the cells were proliferating, and after 6 hours of maturation.

2015-04-24 | E-GEOD-62647 | biostudies-arrayexpress

The histone methyltransferase Setd8 represses Gata2 expression and regulates erythroid maturation

2015-04-24 | GSE62647 | GEO

Effect of SETD8/PR-Set7 knockdown on gene expression profiles in human fibroblasts

Project description:Cellular senescence is an ireversible growth arrest with alterd metabolic potentials including DNA, RNA and protein dynamics. We found that loss of the SETD8/PR-Set7 methyltransferase, which catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1), induces senescence in human fibroblasts. To investigate the role of SETD8 in cellular senescence, we performed a microarray-based transcriptomic analysis in SETD8-knockdown cells. Our results demonstrate that SETD8 links the epigenomic gene regulation to senescence-associated metabolic remodeling.

2017-03-30 | GSE86545 | GEO

SetD8 Knockdown in M-CM-^_-estradiol-treated (24 h) G1E-ER-GATA-1 cells

Project description:The establishment and maintenance of cell type-specific transcriptional programs require an ensemble of broadly expressed chromatin remodeling and modifying enzymes. Many questions remain unanswered regarding the contributions of these enzymes to specialized genetic networks that control critical processes such as lineage commitment and cellular differentiation. We have been addressing this problem in the context of erythrocyte development driven by the transcription factor GATA-1 and its coregulator Friend of GATA-1 (FOG-1). As certain GATA-1 target genes have little to no FOG-1 requirement for expression, presumably additional coregulators can mediate GATA-1 function. Using a genetic complementation assay and RNA interference in GATA-1-null cells, we demonstrate a vital link between GATA-1 and the histone H4 lysine 20 methyltransferase PR-Set7/SetD8 (SetD8). GATA-1 selectively induced H4 monomethylated lysine 20 at repressed, but not activated, loci, and endogenous SetD8 mediated GATA-1-dependent repression of a cohort of its target genes. GATA-1 utilized different combinations of SetD8, FOG-1, and the FOG-1-interacting Nucleosome Remodeling and Deacetylase (NuRD) complex component Mi2b to repress distinct target genes. Implicating SetD8 as a context-dependent GATA-1 corepressor expands the repertoire of coregulators mediating establishment/maintenance of the erythroid cell genetic network and provides a biological framework for dissecting the cell type-specific functions of this important coregulator. We propose a coregulator matrix model in which distinct combinations of chromatin regulators are required at different GATA-1 target genes, and the unique attributes of the target loci mandate these combinations. 3 SetD8 knockdown samples were compared to 3 control samples

2013-07-24 | E-GEOD-49174 | biostudies-arrayexpress

The histone methyltransferase Setd8 alters the chromatin landscape and regulates the expression of key transcription factorsduring erythroid differentiation

Project description:SETD8 is the sole methyltransferase capable of mono-methylating histone H4, lysine 20. SETD8 is highly expressed in erythroid cells and erythroid deletion of Setd8 is embryonic lethal by embryonic day 11.5 (E11.5) due to profound anemia, suggesting it has an erythroid-specific function. To gain insights into the function of SETD8 during erythroid differentiation, we performed ATAC-seq on sorted populations of E10.5 Setd8 null and control erythroblasts. Accessibility profiles were integrated with expression changes and a mark of heterochromatin (H3K27me3) performed in wild type E10.5 erythroblasts to further understand the role of SETD8 in erythropoiesis. Data integration identified regions of greater chromatin accessibility in Setd8 null cells that co-located with H3K27me3 in wild type E10.5 erythroblasts suggesting that these regions, and their associated genes, are repressed during normal erythropoiesis. Pathway analysis of genes identified through data integration revealed stemness-related pathways. Among those genes were multiple transcriptional regulators active in multipotent progenitors but repressed during erythroid differentiation including Hhex, Hlx, and Gata2. Consistent with a role for SETD8 in erythroid specification, SETD8 expression is upregulated upon erythroid commitment, and Setd8 disruption impairs erythroid colony forming ability. Taken together, our results suggest that Setd8 is important for the establishment of appropriate patterns of gene expression during erythroid differentiation.

2020-03-01 | GSE138106 | GEO

GEMM CRC collection analysis

Project description:A collection of genetically engineered mouse models (GEMM) of colorectal cancer (CRC) were created, and primary tumors from these GEMMs were analyzed. Primary CRC tumors from these GEMMs were genotyped to confirm that they contain the core genetic lesions of interest, including APC, P53, KRAS, and BRAF. Primary tumors from GEMMs with combinations of lesions of interest were analyzed by whole genome expression, and their expression profiles were compared to determine how they segregate. Signatures were then generated from GEMM tumors of interest and compared to human clinical datasets with expression and outcome data. Primary tumors from CRC GEMMs with different combinations of mutant alleles of interested were generated and analyzed. Alleles include mutant forms of APC (A), P53 (P), KRAS (K) and BRAF (B).

2014-07-01 | E-GEOD-50794 | biostudies-arrayexpress

Transcription profiling by array of human colorectal cancer SW620 cells upon MSX1 depletion.

Project description:The first step in the development of human colorectal cancer (CRC) is the aberrant hyperactivation of the Wnt signaling pathway, predominantly caused by inactivating mutations in the adenomatous polyposis coli (APC) gene encoding an essential tumor suppressor. In order to identify genes affected by Apc loss, expression profiling of intestinal epithelium isolated from mice harboring the conditional allele of the gene was performed. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Subsequently, the expression pattern of human MSX1 was examined in a collection of colonic tumors. The MSX1 mRNA level was increased in all types of human intestinal neoplasia tested. In order to identify genes affected by MSX1 loss, expression profiling of human colorectal cancer cells SW620 upon MSX1 gene depletion was performed.

2019-11-01 | E-MTAB-6928 | biostudies-arrayexpress

Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer

Project description:The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the re-establishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals, and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC Analysis of RNA isolated from colon polyps that presented in shAPC or shAPC/Kras mice as compared to shRenilla (neutral) mouse colon mucosa

2015-06-18 | E-GEOD-67186 | biostudies-arrayexpress

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