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APE1 controls DICER1 expression through functional regulation of miRNA33a and miRNA130b: a novel hypothesis for NSCLC cancer progression [NanoString]

ABSTRACT: APE1 controls DICER1 expression through functional regulation of miRNA33a and miRNA130b: a novel hypothesis for NSCLC cancer progression [NanoString]

PROVIDER: PRJNA701901 | ENA |

REPOSITORIES: ENA

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APE1 controls DICER1 expression through functional regulation of miRNA33a and miRNA130b: a novel hypothesis for NSCLC cancer progression [NanoString]

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

APE1 controls DICER expression through functional regulation of miRNA33a: a novel hypothesis for NSCLC cancer progression

Project description:APE1 controls DICER expression through functional regulation of miRNA33a: a novel hypothesis for NSCLC cancer progression

| PRJNA701898 | ENA

APE1 controls DICER expression through functional regulation of miRNA33a: a novel hypothesis for NSCLC cancer progression [RNA-Seq]

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

APE1 controls DICER expression through functional regulation of miRNA33a: a novel hypothesis for NSCLC cancer progression [RNA-Seq]

Project description:APE1 controls DICER expression through functional regulation of miRNA33a: a novel hypothesis for NSCLC cancer progression [RNA-Seq]

| PRJNA701559 | ENA

Gene expression influenced by human APE1 and mouse Ape1 in a mouse embryonic fibroblast line.

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

APE1 controls DICER1 expression in NSCLC through miR-33a and miR-130b.

Project description:Increasing evidence suggests different, not completely understood roles of microRNA biogenesis in the development and progression of lung cancer. The overexpression of the DNA repair protein apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an important cause of poor chemotherapeutic response in lung cancer and its involvement in onco-miRNAs biogenesis has been recently described. Whether APE1 regulates miRNAs acting as prognostic biomarkers of lung cancer has not been investigated, yet. In this study, we analyzed miRNAs differential expression upon APE1 depletion in the A549 lung cancer cell line using high-throughput methods. We defined a signature of 13 miRNAs that strongly correlate with APE1 expression in human 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. Functional enrichment analysis of this signature revealed its biological relevance in cancer cell proliferation and survival. We validated DICER1 as a direct functional target of the APE1-regulated miRNA-33a-5p and miR-130b-3p. Importantly, IHC analyses of different human tumors confirmed a negative correlation existing between APE1 and Dicer1 protein levels. DICER1 downregulation represents a prognostic marker of cancer development but the mechanisms at the basis of this phenomenon are still completely unknown. Our findings, suggesting that APE1 modulates DICER1 expression via miR-33a and miR-130b, reveal new mechanistic insights on DICER1 regulation, which are of relevance in lung cancer chemoresistance and cancer invasiveness.

| S-EPMC9314295 | biostudies-literature

Phosphorylated nuclear DICER1 promotes open chromatin state and gastric cell fate in lung adenocarcinomas [Nanostring]

Project description:DICER1 canonically regulates micro(mi)RNA-mediated epithelial-to-mesenchymal transition (EMT) in lung adenocarcinomas (LUADs). We discovered that KRAS/ERK pathway phosphorylates DICER1 causing its nuclear translocation; phosphomimetic Dicer1 contributes to tumorigenesis in mice. Mechanisms through which phospho-DICER1 regulates tumor progression remain undefined. Here, we show that phospho-DICER1 is expressed in invasive human LUADs and promotes late-stage tumor progression in mice with oncogenic Kras, independent of miRNAs and EMT. Strikingly, in mice, we observed that the AT2 tumor cells with phospho-DICER1 express endodermal (gastric) genes and display an open chromatin state such that there are sub-populations of tumors cells with alveolar-endodermal or only endodermal identity. Importantly, we also observed expression of gastric genes in human LUADs with phospho-DICER1. Mechanistically, we identify a chromatin-DICER1 nuclear complex comprised of Mediator complex subunit 12, CBX1, MACROH2A.1 and transcriptional regulators. Together, we propose that phosphorylated-nuclear DICER1 leads to lineage reprogramming of AT2 tumor cells to mediate lung cancer progression.

2023-08-08 | GSE228966 | GEO

APE1 knock-in

Project description:APE1/Ref-1 protects cells from oxidative stress by acting as a central enzyme in base excision repair pathways of DNA lesions and through its independent activity as a redox transcriptional co-activator. To dissect between redox- and DNA-repair-mediated effects, here we performed transcription profiling of knock-in experiments using wild type and mutations C65S and 31-34A.

2011-10-01 | E-MEXP-2941 | biostudies-arrayexpress

Proximity Proteomics Revealed Dicer1 and Transporters as Client Proteins of Aha1

Project description:Co-chaperone Aha1 activates HSP90 ATPase to promote the folding of client proteins. However, the client proteins of Aha1 are largely unknown. By employing ascorbate peroxidase (APEX) based proximity labeling, we identified 32 proximity proteins of HSP90 that are modulated by genetic depletion of Aha1. Among them, Dicer1 is one of the top-ranked proteins, which were further confirmed by streptavidin pull-down followed by Western blot analysis, demonstrating the reliability of the approach. Flag pull-down result showed interactions between endogenous HSP90 and Dicer1 and Aha1. The Dicer1 level is regulated synergistically by Aha1 and HSP90. Maturation-dependent interaction results showed a preferential binding of Aha1 and HSP90 to nascently translated Dicer1. Reconstitution of Aha1-depleted cells with WT Aha1 restored Dicer1 level, while the HSP90-binding-defective E67K mutant exhibited partial restoration. Moreover, knockdown of Aha1 and inhibition of HSP90 can diminish the levels of mature miRNA, let-7b and mir-30a. Overall, our study uncovers, for the first time, Dicer1 and transporter proteins as clients of Aha1 and HSP90.

2022-11-19 | PXD028980 | Pride