Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA197286 | ENA |
REPOSITORIES: ENA
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Project description:The presence of oxidized DNA lesions, such as 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic sites (AP sites), has been described as epigenetic signals that are involved in gene expression control. In mammals, Apurinic-apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is the main AP endonuclease of the base excision repair (BER) pathway and is involved in active demethylation processes. In addition, APE1/Ref-1, through its redox function, regulates several transcriptional factors. However, the transcriptional control targets of each APE1 function are not completely known. In this study, a transcriptomic approach was used to investigate the effects of chemical inhibition of APE1/Ref-1 redox or DNA repair functions by E3330 or methoxyamine (MX) in an inflammatory cellular model. Under lipopolysaccharide (LPS) stimulation, both E3330 and MX reduced the expression of some cytokines and chemokines. Interestingly, E3330 treatment reduced cell viability after 48 h of the treatment. Genes related to inflammatory response and mitochondrial processes were downregulated in both treatments. In the E3330 treatment, RNA processing and ribosome biogenesis genes were downregulated, while they were upregulated in the MX treatment. Furthermore, in the E3330 treatment, the cellular stress response was the main upregulated process, while the cellular macromolecule metabolic process was observed in MX-upregulated genes. Nuclear respiratory factor 1 (NRF1) was predicted to be a master regulator of the downregulated genes in both treatments, while the ETS transcription factor ELK1 (ELK1) was predicted to be a master regulator only for E3330 treatment. Decreased expression of ELK1 and its target genes and a reduced 28S/18S ratio were observed, suggesting impaired rRNA processing. In addition, both redox and repair functions can affect the expression of NRF1 and GABPA target genes. The master regulators predicted for upregulated genes were YY1 and FLI1 for the E3330 and MX treatments, respectively. In summary, the chemical inhibition of APE1/Ref-1 affects gene expression regulated mainly by transcriptional factors of the ETS family, showing partial overlap of APE1 redox and DNA repair functions, suggesting that these activities are not entirely independent. This work provides a new perspective on the interaction between APE1 redox and DNA repair activity in inflammatory response modulation and transcription.
2021-08-29 | GSE182813 | GEO
Project description:The overexpression of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) is an important cause of poor outcome and its expression is able to predict the progression-free and overall survival in patients receiving platinum-containing chemotherapy. Recently, we have demonstrated APE1 involvement in miRNA biogenesis related to cancer progression.
2022-08-03 | GSE166664 | GEO
Project description:To investigate the possible role of Ape1/Ref-1 in tumorigenicity of colon cancer and explored the oncogenic mechanism of Ape1/Ref-1 in colon cancer cells.
2013-04-17 | GSE45912 | GEO
Project description:To investigate the possible role of Ape1/Ref-1 in tumorigenicity of colon cancer and explored the oncogenic mechanism of Ape1/Ref-1 in colon cancer cells. Control and Ref-1 overexpressing SW480cells, control and Ref-1-deficient SW480 cells. Duplicate
2013-04-17 | E-GEOD-45912 | biostudies-arrayexpress
Project description:Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in various cancers, including LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, correlates with poor prognosis in LUAD patients strongly. Using human LUAD cell models and a KRAS-driven genetically engineered mouse model (GEMM), we show that APE1 deletion hampers cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes CPS1 and ARG2 by modulating the presence of G-quadruplex (G4) structures in their promoter regions. Loss of APE1 disrupts the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which can be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1’s role in metabolic regulation via G4-mediated transcription, providing a potential therapeutic target LUAD patients with elevated APE1 expression.
2024-12-06 | GSE245172 | GEO
Project description:Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in various cancers, including LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, correlates with poor prognosis in LUAD patients strongly. Using human LUAD cell models and a KRAS-driven genetically engineered mouse model (GEMM), we show that APE1 deletion hampers cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes CPS1 and ARG2 by modulating the presence of G-quadruplex (G4) structures in their promoter regions. Loss of APE1 disrupts the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which can be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1’s role in metabolic regulation via G4-mediated transcription, providing a potential therapeutic target LUAD patients with elevated APE1 expression.
2024-12-06 | GSE245168 | GEO
Project description:Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in various cancers, including LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, correlates with poor prognosis in LUAD patients strongly. Using human LUAD cell models and a KRAS-driven genetically engineered mouse model (GEMM), we show that APE1 deletion hampers cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes CPS1 and ARG2 by modulating the presence of G-quadruplex (G4) structures in their promoter regions. Loss of APE1 disrupts the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which can be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1’s role in metabolic regulation via G4-mediated transcription, providing a potential therapeutic target LUAD patients with elevated APE1 expression.
2024-12-06 | GSE245167 | GEO
Project description:Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in various cancers, including LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, correlates with poor prognosis in LUAD patients strongly. Using human LUAD cell models and a KRAS-driven genetically engineered mouse model (GEMM), we show that APE1 deletion hampers cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes CPS1 and ARG2 by modulating the presence of G-quadruplex (G4) structures in their promoter regions. Loss of APE1 disrupts the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which can be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1’s role in metabolic regulation via G4-mediated transcription, providing a potential therapeutic target LUAD patients with elevated APE1 expression.
2024-12-06 | GSE271726 | GEO
Project description:Breast cancer is one of the leading causes of cancer-related mortality in women. NOTCH signaling is a well conserved pathway which not only plays critical roles in normal development, but also in cancer progression. One of the Notch ligand, JAGGED1 is overexpressed in about 30% of breast cancer patients. However, the role of JAGGED1 in breast tumorigenesis has not been rigorously examined. By utilizing genetic engineered mouse models of mammary specific Jagged1 expression or knockout, we discover that Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Jagged1 expression leads to increased infiltration of tumor associated macrophages and decreased presentation of T cells within tumor microenvironment. Depletion of macrophages or T cells by neutralizing antibodies diminishes the tumor-promoting effect caused by Jagged1. Mechanistically, Jagged1 activates Notch signaling in tumor cells, leads to increased expression and secretion of multiple cytokines, including IL-6 and WISP. These cytokines help recruit macrophages into the tumor microenvironment. Macrophages crosstalk with infiltrated T cells and inhibit their cytotoxic killing on tumor cells. In triple negative breast cancer patient samples, high expression level of JAGGED1 correlates with increased macrophage infiltration and decreased T cell infiltration within tumor tissues. JAGGED1 also promotes tumor progression in several other solid cancer types, including melanoma, and colon cancer in a T cell dependent manner. Co-administration of immune checkpoint inhibitor, PD-1 antibody with gamma-secretase inhibitor (GSI) significantly inhibits tumor growth. These findings identify a unique oncogenic crosstalk between tumor derived JAGGED1, Macrophages, and T cells to promote tumor progression.
2022-03-08 | GSE161769 | GEO
Project description:Breast cancer is one of the leading causes of cancer-related mortality in women. NOTCH signaling is a well conserved pathway which not only plays critical roles in normal development, but also in cancer progression. One of the Notch ligand, JAGGED1 is overexpressed in about 30% of breast cancer patients. However, the role of JAGGED1 in breast tumorigenesis has not been rigorously examined. By utilizing genetic engineered mouse models of mammary specific Jagged1 expression or knockout, we discover that Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Jagged1 expression leads to increased infiltration of tumor associated macrophages and decreased presentation of T cells within tumor microenvironment. Depletion of macrophages or T cells by neutralizing antibodies diminishes the tumor-promoting effect caused by Jagged1. Mechanistically, Jagged1 activates Notch signaling in tumor cells, leads to increased expression and secretion of multiple cytokines, including IL-6 and WISP. These cytokines help recruit macrophages into the tumor microenvironment. Macrophages crosstalk with infiltrated T cells and inhibit their cytotoxic killing on tumor cells. In triple negative breast cancer patient samples, high expression level of JAGGED1 correlates with increased macrophage infiltration and decreased T cell infiltration within tumor tissues. JAGGED1 also promotes tumor progression in several other solid cancer types, including melanoma, and colon cancer in a T cell dependent manner. Co-administration of immune checkpoint inhibitor, PD-1 antibody with gamma-secretase inhibitor (GSI) significantly inhibits tumor growth. These findings identify a unique oncogenic crosstalk between tumor derived JAGGED1, Macrophages, and T cells to promote tumor progression.
2022-03-08 | GSE161768 | GEO