NCOR1 sustains CRC growth and protects from cellular senescence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA728731 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14485870_1.fastq.gz | Fastqsanger.gz | |||
| SRR14485870_2.fastq.gz | Fastqsanger.gz | |||
| SRR14485871_1.fastq.gz | Fastqsanger.gz | |||
| SRR14485871_2.fastq.gz | Fastqsanger.gz | |||
| SRR14485872_1.fastq.gz | Fastqsanger.gz |
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Project description:The nuclear corepressor NCOR1 is a transcriptional repressor that regulates gene expression by associating with nuclear receptors or transcription factors such as AP-1 and NF-KB. The objective of this work was to determine how NCOR1 regulates proliferation and inflammatory response in human colorectal cancer cell lines. We observed that upon targeting NCOR1 expression from the use of shRNAs, Caco-2/15 and HT-29 colorectal cancer cells stopped proliferating with characteristics of being senescent. In addition, we noticed an induction of inflammatory molecules associated with SASP in these cells. We analyzed the transcriptome of shNCOR1_655 cells and identified the SOX2 pluripotency factor as being induced when the expression of NCOR1 is decreased. This transcriptome was also enriched in molecules normally associated with migration and invasion biological processes.
2021-09-15 | GSE174204 | GEO
Project description:NCOR1 is a corepressor that mediates transcriptional repression through its association with nuclear receptors and specific transcription factors. Some evidence supports a role for NCOR1 in neonatal intestinal epithelium maturation and the maintenance of epithelial integrity during experimental colitis in mice. We hypothesized that NCOR1 could control colorectal cancer cell proliferation and tumorigenicity. Conditional intestinal epithelial deletion of Ncor1 in ApcMin/+ mice resulted in a significant reduction in polyposis. RNAi targeting of NCOR1 in Caco-2/15 and HT-29 cell lines led to a reduction in cell growth, characterized by cellular senescence associated with a secretory phenotype. Tumor growth of HT-29 cells was reduced in the absence of NCOR1 in the mouse xenografts. RNA-seq transcriptome profiling of colon cancer cells confirmed the senescence phenotype in the absence of NCOR1 and predicted the occurrence of a pro-migration cellular signature in this context. SOX2, a transcription factor essential for pluripotency of embryonic stem cells, was induced under these conditions. In conclusion, depletion of NCOR1 reduced intestinal polyposis in mice and caused growth arrest, leading to senescence in human colorectal cell lines. The acquisition of a pro-metastasis signature in the absence of NCOR1 could indicate long-term potential adverse consequences of colon-cancer-induced senescence.
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Project description:DNA methylation protects cancer cells against non-canonical senescence
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Project description:DNA methylation protects cancer cells against non-canonical senescence
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Project description:Aberrant DNA methylation patterns are a hallmark of human cancers, prompting targeting of DNA methylation machinery to be explored as an anti-tumor strategy. DNA methyltransferase 1 (DNMT1) and ubiquitin like With PHD and Ring finger domains 1 (UHRF1) are crucial enzymes for DNA methylation maintenance. Unlike DNMT1, UHRF1 is overexpressed in most cancers and is a proven oncogene in vivo. Our previous work revealed that the degree of DNA methylation loss induced by UHRF1 depletion is more severe than DNMT1 depletion in colorectal cancer cells, indicating that targeting UHRF1 may be a more effective approach. Using an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, we monitored the long-term effects of removing UHRF1 and/or DNMT1 in cancer cells, deciphering the mechanistic basis through bioinformatic tools. We found that chronic DNA demethylation triggers cancer cells to undergo cellular senescence. The loss of UHRF1 results in a more rapid and profound senescence phenotype than DNMT1 loss. Intriguingly, this senescence is not accompanied by DNA damage and functions independently of canonical senescence pathways such as p53 and p16/pRB. Non-canonical pathway investigations revealed that cytosolic p21 accumulation contributes to antiapoptosis during senescence. The suppression of cyclic GMP-AMP synthase (cGAS) also alleviates the senescence-associated secretory phenotype (SASP) and lysosomal activity, and this process is independent of stimulator of interferon genes (STING). Finally, xenograft experiments verified our findings in vivo. Our results highlight how DNA methylation protects cancer cells from non-canonical senescence and demonstrate the potential of targeting UHRF1 as a novel avenue for anticancer treatments.
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Project description:Aberrant DNA methylation patterns are a hallmark of human cancers, prompting targeting of DNA methylation machinery to be explored as an anti-tumor strategy. DNA methyltransferase 1 (DNMT1) and ubiquitin like With PHD and Ring finger domains 1 (UHRF1) are crucial enzymes for DNA methylation maintenance. Unlike DNMT1, UHRF1 is overexpressed in most cancers and is a proven oncogene in vivo. Our previous work revealed that the degree of DNA methylation loss induced by UHRF1 depletion is more severe than DNMT1 depletion in colorectal cancer cells, indicating that targeting UHRF1 may be a more effective approach. Using an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, we monitored the long-term effects of removing UHRF1 and/or DNMT1 in cancer cells, deciphering the mechanistic basis through bioinformatic tools. We found that chronic DNA demethylation triggers cancer cells to undergo cellular senescence. The loss of UHRF1 results in a more rapid and profound senescence phenotype than DNMT1 loss. Intriguingly, this senescence is not accompanied by DNA damage and functions independently of canonical senescence pathways such as p53 and p16/pRB. Non-canonical pathway investigations revealed that cytosolic p21 accumulation contributes to antiapoptosis during senescence. The suppression of cyclic GMP-AMP synthase (cGAS) also alleviates the senescence-associated secretory phenotype (SASP) and lysosomal activity, and this process is independent of stimulator of interferon genes (STING). Finally, xenograft experiments verified our findings in vivo. Our results highlight how DNA methylation protects cancer cells from non-canonical senescence and demonstrate the potential of targeting UHRF1 as a novel avenue for anticancer treatments.
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Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function. This SuperSeries is composed of the SubSeries listed below.
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Project description:Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing is observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover a pivotal role of the human SIRT6 enzyme in pericentric transcriptional silencing, and this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, histone H3 lysine K18 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, RNAi-depletion of these transcripts rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and H3K18Ac regulation at heterochromatin, and demonstrate the pathogenic role of de-regulated pericentric transcription in aging- and cancer- related cellular dysfunction. H3K18ac, H3K9ac, H3K9me3, H3K56ac and Input ChIP-seq for U2OS cell
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Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
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