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 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 proteosome-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. Project financed under DIOSCURI, a program initiated by the Max Planck Society, jointly managed with the National Science Centre in Poland, and mutually funded by Polish Ministry of Science and Higher Education and German Federal Ministry of Education and Research [2019/02/H/NZ1/00002 to G.M.]. The project was co-financed Polish National Agency for Academic Exchange within Polish Returns Programme [PPN/PPO/2020/1/00006/U/00001] as well as National Science Centre [2021/01/1/NZ1/00001 and 2023/49/B/NZ1/02456 to G.M.]. This work was financed by the statutory funding of the International Institute of Molecular and Cell Biology in Warsaw. This research was performed thanks to the IIMCB IN-MOL-CELL Infrastructure (RRID:SCR_021630) funded by the European Union – NextGenerationEU under National Recovery and Resilience Plan. IN-MOL-CELL Infrastructure was also funded by the European Union under Horizon Europe (Project 101059801—RACE) and by RACE-PRIME project carried out within the IRAP program of the Foundation for Polish Science co-financed by the European Union under the European Funds for Smart Economy 2021–2027 (FENG). This work was funded by the National Science Centre Poland grant number 2019/35/B/NZ4/04355 to MD. J.R. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC 2008 – 390540038 – UniSysCat and project 449713269. The Wellcome Centre for Cell Biology is supported by core funding from the Wellcome Trust (Grant number 203149). C.S. was funded by Wellcome instrument grant 108504. This work was supported by funding for the Wellcome Discovery Research Platform for Hidden Cell Biology (226791), and we gratefully acknowledge support from the Proteomics core.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Gracjan Michlewski  

LAB HEAD: Gracjan Michlewski

PROVIDER: PXD050698 | Pride | 2024-12-20

REPOSITORIES: Pride