APE1 controls DICER expression through functional regulation of miRNA33a: a novel hypothesis for NSCLC cancer progression [RNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE166664 | GEO | 2022/08/03
REPOSITORIES: GEO
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Project description:Lung cancer is the leading cause of cancer death worldwide. The lack of specific and sensitive methods for early diagnosis as well as inadequate targeted therapies contribute to poor outcomes. A growing body of evidences suggests different roles of microRNAs including development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) is an important cause of poor chemotherapeutic 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. In this article, we report the identification of miRNAs that are modulated in lung cancer cells upon APE1 silencing. We defined a miRNA signature consisting of the 13 miRNAs, which strongly correlates with APE1 expression in lung cancer: miR-1246, miR-4488, miR-24, miR-183, miR-660, miR-130b, miR-543, miR-200c, miR-376c, miR-218, miR-146a, miR-92b and miR-33a. Gene ontology annotation and pathway analysis of the miRNA signature revealed its biological significance in cancer proliferation and survival. Among the miRNAs downregulated by APE1 is miRNA-33a-5p which targets Dicer, a major miRNA biogenesis gene whose expression is found to be downregulated in several tumours. We here validated Dicer as a direct functional target of miR-33a and profiled miR-33a, DICER and APE1 expression in clinical samples. Our findings suggest that APE1 may promote lung cancer progression through modulation of Dicer expression via miR-33a regulation. Our findings reveal new mechanistic insight into how APE1 functions in tumor biology.
2022-08-03 | GSE166749 | 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 | 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 | GSE271726 | 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:The base excision repair (BER) Apurinic/apyrimidinic endonuclease 1 (APE1) enzyme is endowed with several non-repair activities, such as the cell response to genotoxic stress, the regulation of gene expression and miRNAs processing. We recently demonstrated that APE1 can be actively secreted by mammalian cells through exosomes. The role of APE1 in exosomes is still unknown, especially regarding the molecular mechanism involving small non-coding RNAs vesicular secretion. miRNAs loading into exosomes is a regulated and selective process, since not all the expressed miRNAs are indistinctly conveyed into exosomes. Through a dedicated transcriptomic analysis on cellular and vesicular small RNAs, we identified secreted miRNAs characterized by enriched sequence motifs and possible binding sites for APE1. In 50 out of 53 DE-miRNA precursors, we surprisingly found EXO motifs and proved that APE1 cooperates with hnRNPA2B1 for the EV-sorting of a subsets of miRNAs, including miR-1246, through a direct binding to GGAG stretch. We provide evidence of a new post-transcriptional role for this ubiquitous DNA-repair enzyme towards miRNAs secretion mechanisms, that could be exploited to interfere with tumor microenvironment.
2024-07-24 | GSE230874 | GEO
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:APE1 (AP-endonuclease 1) is an essential DNA repair protein but also it functions as a gene regulatory protein. A unique mouse embyonic fibroblast with almost undetectable levels of APE1 was isolated. Three isogenic derivatives of this cell line that contain either of the control vector, the human APE1 cDNA, and mouse Ape1 cDNA were analyzed for their global gene expression using Affymetrix mouse ST 2.0 chip set.
2016-01-31 | GSE55765 | GEO
Project description:APE1 controls DICER expression through functional regulation of miRNA33a: a novel hypothesis for NSCLC cancer progression
| PRJNA701898 | ENA
Project description:Apurinic/apyrimidinic endonuclease/redox factor-1 (Ape1/Ref-1) activates Notch signaling through Jagged1 expression and promotes colon cancer progression
| PRJNA197286 | ENA