Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels
Abstract Background HuR/ELAV1, a ubiquitous RNA-binding protein, belongs to the RNA-binding protein family and is crucial for stabilizing and regulating the translation of various mRNA targets, influencing gene expression. Elevated HuR levels are associated with multiple disorders, including cancer...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-01-01
|
| Series: | BMC Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12915-025-02131-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585354058661888 |
|---|---|
| author | Nathalie Idlin Sivakumar Krishnamoorthy Magdalena Wolczyk Mouad Fakhri Michal Lechowski Natalia Stec Jacek Milek Pratik Kumar Mandal Jaroslaw Cendrowski Christos Spanos Magdalena Dziembowska Katarzyna Mleczko-Sanecka Juri Rappsilber Gracjan Michlewski |
| author_facet | Nathalie Idlin Sivakumar Krishnamoorthy Magdalena Wolczyk Mouad Fakhri Michal Lechowski Natalia Stec Jacek Milek Pratik Kumar Mandal Jaroslaw Cendrowski Christos Spanos Magdalena Dziembowska Katarzyna Mleczko-Sanecka Juri Rappsilber Gracjan Michlewski |
| author_sort | Nathalie Idlin |
| collection | DOAJ |
| description | Abstract Background HuR/ELAV1, a ubiquitous RNA-binding protein, belongs to the RNA-binding protein family and is crucial for stabilizing and regulating the translation of various mRNA targets, influencing gene expression. Elevated HuR levels are associated with multiple disorders, including cancer and neurodegenerative diseases. Despite the identification of small molecule inhibitors targeting HuR, their detailed characterization remains limited. Recently, Eltrombopag, an FDA-approved drug for immune thrombocytopenic purpura and chemotherapy-induced thrombocytopenia, emerged as a potential HuR inhibitor. However, the specific molecular pathways influenced by both HuR and Eltrombopag are not fully understood. Results Our study demonstrates that Eltrombopag operates via HuR inhibition, affecting gene expression regulation at the posttranscriptional level. We show that both HuR knockout and Eltrombopag treatment modulate iron metabolism by decreasing ferritin heavy chain (FTH1) and light chain (FTL) synthesis while increasing the expression of iron-regulatory protein 2 (IRP2), a key regulator of ferritin translation. Additionally, HuR inhibition reduces the levels of glycoprotein hormones, alpha polypeptide (CGA), a marker associated with hormone-induced tumors, suggesting a potential use of Eltrombopag in treatment of cancers overexpressing CGA. We observed that the main of control is manifested at the level of translation inhibition, with proteasome-mediated regulation also playing an important role. Conclusions These findings uncover novel posttranscriptional mechanisms governed by HuR and its inhibitor, elucidating pathways relevant to HuR-mediated regulation and molecular therapies aimed at targeting this protein. |
| format | Article |
| id | doaj-art-5ce1039d57274c36b9d699c88b7750a4 |
| institution | Kabale University |
| issn | 1741-7007 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj-art-5ce1039d57274c36b9d699c88b7750a42025-01-26T12:52:36ZengBMCBMC Biology1741-70072025-01-0123112110.1186/s12915-025-02131-zEffects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levelsNathalie Idlin0Sivakumar Krishnamoorthy1Magdalena Wolczyk2Mouad Fakhri3Michal Lechowski4Natalia Stec5Jacek Milek6Pratik Kumar Mandal7Jaroslaw Cendrowski8Christos Spanos9Magdalena Dziembowska10Katarzyna Mleczko-Sanecka11Juri Rappsilber12Gracjan Michlewski13International Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawDepartment of Animal Physiology, Faculty of Biology, University of WarsawInternational Institute of Molecular and Cell Biology in WarsawMaria Sklodowska-Curie National Research Institute of OncologyThe Wellcome Centre for Cell Biology, University of EdinburghDepartment of Animal Physiology, Faculty of Biology, University of WarsawInternational Institute of Molecular and Cell Biology in WarsawDepartment of Biotechnology, Technische Universität BerlinInternational Institute of Molecular and Cell Biology in WarsawAbstract Background HuR/ELAV1, a ubiquitous RNA-binding protein, belongs to the RNA-binding protein family and is crucial for stabilizing and regulating the translation of various mRNA targets, influencing gene expression. Elevated HuR levels are associated with multiple disorders, including cancer and neurodegenerative diseases. Despite the identification of small molecule inhibitors targeting HuR, their detailed characterization remains limited. Recently, Eltrombopag, an FDA-approved drug for immune thrombocytopenic purpura and chemotherapy-induced thrombocytopenia, emerged as a potential HuR inhibitor. However, the specific molecular pathways influenced by both HuR and Eltrombopag are not fully understood. Results Our study demonstrates that Eltrombopag operates via HuR inhibition, affecting gene expression regulation at the posttranscriptional level. We show that both HuR knockout and Eltrombopag treatment modulate iron metabolism by decreasing ferritin heavy chain (FTH1) and light chain (FTL) synthesis while increasing the expression of iron-regulatory protein 2 (IRP2), a key regulator of ferritin translation. Additionally, HuR inhibition reduces the levels of glycoprotein hormones, alpha polypeptide (CGA), a marker associated with hormone-induced tumors, suggesting a potential use of Eltrombopag in treatment of cancers overexpressing CGA. We observed that the main of control is manifested at the level of translation inhibition, with proteasome-mediated regulation also playing an important role. Conclusions These findings uncover novel posttranscriptional mechanisms governed by HuR and its inhibitor, elucidating pathways relevant to HuR-mediated regulation and molecular therapies aimed at targeting this protein.https://doi.org/10.1186/s12915-025-02131-zHuRELAVL1EltrombopagIron metabolism |
| spellingShingle | Nathalie Idlin Sivakumar Krishnamoorthy Magdalena Wolczyk Mouad Fakhri Michal Lechowski Natalia Stec Jacek Milek Pratik Kumar Mandal Jaroslaw Cendrowski Christos Spanos Magdalena Dziembowska Katarzyna Mleczko-Sanecka Juri Rappsilber Gracjan Michlewski Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels BMC Biology HuR ELAVL1 Eltrombopag Iron metabolism |
| title | Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels |
| title_full | Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels |
| title_fullStr | Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels |
| title_full_unstemmed | Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels |
| title_short | Effects of genetic ablation and pharmacological inhibition of HuR on gene expression, iron metabolism, and hormone levels |
| title_sort | effects of genetic ablation and pharmacological inhibition of hur on gene expression iron metabolism and hormone levels |
| topic | HuR ELAVL1 Eltrombopag Iron metabolism |
| url | https://doi.org/10.1186/s12915-025-02131-z |
| work_keys_str_mv | AT nathalieidlin effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT sivakumarkrishnamoorthy effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT magdalenawolczyk effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT mouadfakhri effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT michallechowski effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT nataliastec effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT jacekmilek effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT pratikkumarmandal effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT jaroslawcendrowski effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT christosspanos effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT magdalenadziembowska effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT katarzynamleczkosanecka effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT jurirappsilber effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels AT gracjanmichlewski effectsofgeneticablationandpharmacologicalinhibitionofhurongeneexpressionironmetabolismandhormonelevels |