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ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform.

ABSTRACT: The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 promoter region to enhance the global NEAT1 transcriptional activity. Importantly, by stabilizing CPSF6, a protein that selectively activates the post-transcriptional generation of the short isoform of NEAT1, as well as by direct binding and stabilization of the short isoform of NEAT1, ALYREF selectively fine-tunes the expression of the short NEAT1 isoform. Overall, our study describes ALYREF as a novel factor contributing to breast carcinogenesis and identifies novel molecular mechanisms of regulation the two isoforms of NEAT1.

SUBMITTER: Klec C

PROVIDER: S-EPMC9249705 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform.

Klec Christiane C Knutsen Erik E Schwarzenbacher Daniela D Jonas Katharina K Pasculli Barbara B Heitzer Ellen E Rinner Beate B Krajina Katarina K Prinz Felix F Gottschalk Benjamin B Ulz Peter P Deutsch Alexander A Prokesch Andreas A Jahn Stephan W SW Lellahi S Mohammad SM Perander Maria M Barbano Raffaela R Graier Wolfgang F WF Parrella Paola P Calin George Adrian GA Pichler Martin M

Cellular and molecular life sciences : CMLS 20220701 7

The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profil ...[more]

PMID: 35776213

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Project description:BackgroundInflammatory bowel disease (IBD) is a chronic nonspecific intestinal disease. Our previous work showed that long non-coding RNA (LncRNA) nuclear enriched abundant transcript 1 (NEAT1) plays an important role in IBD. In the current study, we aimed to explore the underlying mechanism by which NEAT1 participates in the development of the disease.MethodsReal-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to detect the expression of NEAT1 and tumor necrosis factor superfamily member 1B (TNFRSF1B) in clinical specimens and dextran sulfate sodium (DSS) colitis mice. Inflammatory cell models were established by stimulating human normal intestinal epithelial cell line NCM460 and human colon cancer cell line HT-29 with tumor necrosis factor alpha (TNF-α). Expressions of inflammatory cytokines such as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) were detected by enzyme-linked immunosorbent assay (ELISA) or RT-qPCR, TNFRSF1B, NF-κB p65 and p-NF-κB p65 followed by the knockdown or overexpression of NEAT1 and TNFRSF1B were analyzed by western blotting, and the regulatory effects of NEAT1 on TNFRSF1B were detected by RNA pull-down experiments and RNA-decay assay. The translocation of NF-κB p65 to the nucleus was detected by immunofluorescence.ResultsIn patients' specimens and DSS colitis mouse models, NEAT1 and TNFRSF1B expression were up-regulated compared with the control group. TNF-α stimulation increased NEAT1 and TNFRSF1B expression and activated NF-κB signaling pathway by increasing the translocation of NF-κB p65 to the nucleus. In the presence of TNF-α stimulation, NEAT1 knockdown reduces the expression of TNFRSF1B and the translocation of NF-κB p65, thereby relieves cell inflammation. These effects can be reversed by the overexpression of TNFRSF1B.In addition, NEAT1 is involved in inflammatory response by up-regulating the mRNA levels of TNFRSF1B, and knocking down NEAT1 can alleviate inflammation by down-regulating TNFRSF1B. Moreover, NEAT1 co-precipitates TNFRSF1B mRNA in RNA-pulldown assay, and the presence of NEAT1 stabilizes the mRNA of TNFRSF1B.ConclusionsOur results showed that LncRNA NEAT1 promotes NF-κB p65 translocation and mediates intestinal inflammation by regulating TNFRSF1B.

Project description:The incidence of thyroid nodules has been increasing worldwide; however, there are currently no feasible and robust methods to differentiate malignant thyroid nodules from benign thyroid nodules. The present study aimed to establish a practical method to determine the malignancy of thyroid nodules. Reverse transcription‑quantitative PCR and western blot analyses were performed to compare the levels of long non‑coding RNA nuclear enriched abundant transcript 1 (NEAT1), microRNA (miR)‑9, miR‑124, PTEN and programmed cell death protein 6 (PDCD6) in the peripheral blood and thyroid tissue samples between patients with malignant and benign thyroid nodules. Additionally, a regulatory relationship between NEAT1, miR‑124, miR‑9, PTEN and PDCD6 was established in the present study. The diagnostic value of NEAT1, miR‑124 and miR‑9 was determined using a ROC analysis. The expression levels of NEAT1, PTEN and PDCD6 in peripheral blood and thyroid tissue samples collected from the benign group were higher compared with those in the malignant group, whereas the expression levels of miR‑124 and miR‑9 were lower in the benign group. In the peripheral blood, NEAT1 expression exhibited an area under the curve (AUC) value of 0.8546, whereas miR‑124 and miR‑9 expression had AUC values of 0.7657 and 0.7019, respectively. In the thyroid tissue, NEAT1, miR‑124, and miR‑9 had AUC values of 0.9304, 0.8221 and 0.7757, respectively. Additionally, miR‑9 and miR‑124 expression levels in BCPaP and SW579 cells was decreased after transfection with a NEAT1 expression vector compared with those in cells transfected with the control vector, whereas the expression of PTEN and PDCD6 was upregulated. By contrast, transfection with short hairpin RNA targeting NEAT1 notably increased the expression of miR‑9 and miR‑124 while downregulating the expression of PTEN and PDCD6 compared with that in the control cells. In conclusion, the results of the present study demonstrated that the dysregulation of NEAT1 expression may be used to differentiate benign and malignant thyroid nodules.

Dataset Information

ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform.

Publications

ALYREF, a novel factor involved in breast carcinogenesis, acts through transcriptional and post-transcriptional mechanisms selectively regulating the short NEAT1 isoform.

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