EHMT2-mediated chromatin reprogramming in 5-fluorouracil (5-FU) resistant colorectal cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE314837 | GEO | 2026/03/13
REPOSITORIES: GEO
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Project description:In the present study, we investigated miRNA expression changes caused by aquired chemoresistance to 5-FU or Oxa. 40 and 14 miRNAs were detected as differentially expressed in 5-fluouracil- and oxaliplatin-resistant colorectal HCT116 sublines, respectively. Differentially expressed miRNAs determined in the present study could be applied for further development of diagnostic and therapeutic applications for colorectal cancer carcinoma resistant to 5-FU or Oxa.
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Project description:This study investigates the role of phosphoglycerate dehydrogenase (PHGDH) in 5-fluorouracil (5-FU) chemoresistance in colorectal cancer (CRC). The researchers discovered that PHGDH expression is highly variable in tumor tissues and patient-derived CRC organoids, with elevated PHGDH levels correlating with reduced sensitivity to 5-FU treatment. Through transcriptomic analysis, PHGDH was found to promote activation of the Hedgehog (HH) signaling pathway, which plays a key role in chemoresistance. PHGDH silencing reduces HH activation and increases sensitivity to 5-FU, while PHGDH overexpression has the opposite effect. Significantly, combined treatment with 5-FU and HH pathway inhibitors (JC19 or GANT61) synergistically enhances chemosensitivity in high-PHGDH expressing CRC cells, organoids, and xenograft models. This dual-targeting approach effectively limits tumor growth in mice. The findings establish PHGDH as a potential biomarker for predicting response to 5-FU-based chemotherapy and suggest that targeting the PHGDH-HH axis may represent a promising therapeutic strategy to overcome chemoresistance in CRC.
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Project description:Fluorouracil (5-FU) chemoresistance is an important reason for the postoperative recurrence and poor prognosis of gastric cancer, but there is still no effective way to overcome chemoresistance. Here, by using the CRISPR/Cas9 system, we identify nitrilase family member 2 (NIT2) reverses chemoresistance, regardless of its metabolic function. NIT2 depletion causes H3K14 acetylation (H3K14ac) increase and NF-κB signalling activation, in turn upregulating oxidative phosphorylation (OXPHOS) and promoting chemoresistance. Mechanistically, NIT2 prevents BRD1 from binding histones and releases ING4 to degrade the transcription factor RELA. Upon 5-FU stimulation, the E3 ligase CCNB1IP1 interacts with NIT2 to cause autophagic degradation of NIT2. In addition, NIT2 downregulation correlates with poor prognosis in gastric cancer patients, and this is probably related to the promotion of OXPHOS. Our finding highlights the nonenzymatic function of NIT2 in chemoresistance and show that the blockade of OXPHOS by metformin can enhance chemosensitivity to 5-FU upon loss of NIT2.
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Project description:In this study, we wanted to examine the effects of 5-fluorouracil, a drug used in anticancer treatment, on the proteome of HEK293T cells (human cell culture). HEK293T cells were exposed to 5-fluorouracil (5-FU) using two different incubation strategies. In the first experiment, cells were incubated in 5-FU supplied medium and harvested after 24h acute exposure. The second experiment included a 24h exposure to 5-FU, followed by a recovery phase, were cells were incubated for another 6h in fresh medium without 5-FU. We performed shotgun proteomics of the respective tryptic digest of both experiments and compared the proteome of treated and untreated cells, respectively.
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Project description:5-Fluorouracil (5-FU) is one of the most common drugs used in chemotherapy because of its efficacy and stability. However, 5-FU has been known to work on only 10~15% of colon cancer patients. Therefore, the study of 5-FU sensitivity study is necessary to increase the survival of colon cancer patients. p53 is one of the factors that effect on drug sensitivity. Main function of p53 has been focused on transcription activity in cell death. Numerous drug related studies show that expression of wild-type p53 increases drug sensitivity in various cancer types through inducing apoptotic signaling pathways. Currently, it has been reported that p53 has both transcriptional and non-transcriptional activities in apoptosis. However, most studies about p53 non-transcriptional activities in apoptosis are mainly focused on p53 induced mitochondrial outer membrane permeabilization, triggering the release of pro-apoptotic factors. The chromatin structure and organization have strongly attracted because of their impacts in cellular phenotypes. Recent studies have been shown that changes in chromatin accessibility affect cell phenotypes for external stimuli. Since p53 plays an important role in drug sensitivity and 5-FU is an external stimulus for cancer cells, we hypothesized that p53 may effect on 5-FU sensitivity through different regulation of chromatin accessible regions between TP53-WT and TP53-KO cells. To determine the effect of p53 on chromatin accessibility modification associated with 5-FU sensitivity, ATAC-seq and RNA-seq were performed under 5-FU treatment on TP53-WT as drug sensitive and TP53-KO as drug resistant HCT116 cells. In this study, we found that 5-FU induces chromatin accessibility in both TP53-WT and TP53-KO cells. Moreover, our results show that 5-FU induced chromatin accessibility increases expression of apoptotic genes in TP53-WT HCT116 cells through p53 non-transcriptional activity in nucleus.
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Project description:5-Fluorouracil (5-FU) is one of the most common drugs used in chemotherapy because of its efficacy and stability. However, 5-FU has been known to work on only 10~15% of colon cancer patients. Therefore, the study of 5-FU sensitivity study is necessary to increase the survival of colon cancer patients. p53 is one of the factors that effect on drug sensitivity. Main function of p53 has been focused on transcription activity in cell death. Numerous drug related studies show that expression of wild-type p53 increases drug sensitivity in various cancer types through inducing apoptotic signaling pathways. Currently, it has been reported that p53 has both transcriptional and non-transcriptional activities in apoptosis. However, most studies about p53 non-transcriptional activities in apoptosis are mainly focused on p53 induced mitochondrial outer membrane permeabilization, triggering the release of pro-apoptotic factors. The chromatin structure and organization have strongly attracted because of their impacts in cellular phenotypes. Recent studies have been shown that changes in chromatin accessibility affect cell phenotypes for external stimuli. Since p53 plays an important role in drug sensitivity and 5-FU is an external stimulus for cancer cells, we hypothesized that p53 may effect on 5-FU sensitivity through different regulation of chromatin accessible regions between TP53-WT and TP53-KO cells. To determine the effect of p53 on chromatin accessibility modification associated with 5-FU sensitivity, ATAC-seq and RNA-seq were performed under 5-FU treatment on TP53-WT as drug sensitive and TP53-KO as drug resistant HCT116 cells. In this study, we found that 5-FU induces chromatin accessibility in both TP53-WT and TP53-KO cells. Moreover, our results show that 5-FU induced chromatin accessibility increases expression of apoptotic genes in TP53-WT HCT116 cells through p53 non-transcriptional activity in nucleus.
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Project description:The transcriptional profiles of the HCT116 parental cells following treatment with either 5-FU or SN38 for 24h were assessed. In addition, basal comparisons between HCT116 parental and HCT116 5-FU -resistant and HCT116 SN38-resistant cells were also assessed.
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Project description:This dataset originates from a Proteome Integral Solubility Alteration (PISA) experiment designed to assess how 5-fluorouracil (5-FU) alters protein thermal stability/solubility in MDA-MB-231 cells. Cells were treated with 200 μM 5-FU or DMSO for 2 h, exposed to a temperature gradient, lysed, and soluble proteins from each condition were isolated, digested, and labeled with TMTpro reagents. Labeled peptides were fractionated and analyzed by LC-MS/MS. The raw data were processed with MaxQuant against the human UniProt reference proteome, providing proteome-wide quantitative profiles of 5-FU-induced changes in protein solubility.
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Project description:The extensive drug resistance of hepatocellular carcinoma (HCC) has become the main cause of chemotherapy failure. The mechanisms leading to drug resistance in tumor cells are not well understood. Previous studies demonstrated that plasma membrane proteins play important roles in mediating drug disposal or pharmacokinetics. Therefore, we performed proteomic studies on the composition of 5-fluorouracil (5-Fu) resistant Bel/5Fu cell line and its parent Bel7402 cell line by using an ionic liquid-assisted proteins extraction method with the advantage of extracting plasma membrane proteins to a greater extent. In total, 4,532 unique proteins were quantified and 103 proteins (>2-fold change, p-value <0.05) including 25 plasma membrane proteins showed to be differentially expressed in Bel/5Fu compared with Bel7402. Western blot analysis results were further confirmed that the plasma membrane proteins EPHX1 PLIN2 RAB27B SLC4A2 were up-regulated in Bel/5Fu cells in accordance with the proteomics data. Moreover, cell viability assay and clonogenic survival assay results demonstrated that EPHX1 are closely related to the chemoresistance of Bel/5Fu to 5Fu.
2019-10-19 | PXD015917 |