GAS41 modulates ferroptosis by anchoring NRF2 on chromatin Journal Article
| Authors: | Wang, Z.; Yang, X.; Chen, D.; Liu, Y.; Li, Z.; Duan, S.; Zhang, Z.; Jiang, X.; Stockwell, B. R.; Gu, W. |
| Article Title: | GAS41 modulates ferroptosis by anchoring NRF2 on chromatin |
| Abstract: | YEATS domain-containing protein GAS41 is a histone reader and oncogene. Here, through genome-wide CRISPR-Cas9 screenings, we identify GAS41 as a repressor of ferroptosis. GAS41 interacts with NRF2 and is critical for NRF2 to activate its targets such as SLC7A11 for modulating ferroptosis. By recognizing the H3K27-acetylation (H3K27-ac) marker, GAS41 is recruited to the SLC7A11 promoter, independent of NRF2 binding. By bridging the interaction between NRF2 and the H3K27-ac marker, GAS41 acts as an anchor for NRF2 on chromatin in a promoter-specific manner for transcriptional activation. Moreover, the GAS41-mediated effect on ferroptosis contributes to its oncogenic role in vivo. These data demonstrate that GAS41 is a target for modulating tumor growth through ferroptosis. Our study reveals a mechanism for GAS41-mediated regulation in transcription by anchoring NRF2 on chromatin, and provides a model in which the DNA binding activity on chromatin by transcriptional factors (NRF2) can be directly regulated by histone markers (H3K27-ac). © The Author(s) 2024. |
| Keywords: | adult; controlled study; unclassified drug; human cell; overall survival; promoter region; nonhuman; binding affinity; cell proliferation; proteome; chromosome; mouse; animal tissue; cell viability; gene; gene expression; embryo; protein depletion; protein dna binding; protein protein interaction; protein targeting; transcription initiation; animal experiment; animal model; protein; small interfering rna; lung cancer; in vivo study; in vitro study; protein p53; carcinogenesis; cancer inhibition; oncogene; dna; transcription regulation; ubiquitination; messenger rna; histone; chromatin; histone h3; gene repression; transactivation; reactive oxygen metabolite; down regulation; upregulation; oxidative stress; tumor growth; tumor; dna binding; doxycycline; repressor protein; lipid peroxidation; glutathione; acyltransferase; chromatin assembly and disassembly; acetylation; regulator protein; cell; colony formation; calvasculin; transcription factor nrf2; histone acetylation; anchor; ferroptosis; kelch like ech associated protein 1; cancer; human; female; article; apoptosis inhibitor; glutathione metabolism; crispr-cas9 system; hek293t cell line; nci-h1299 cell line; a-549 cell line; nci-h460 cell line; gene knockout; mrna expression level; protein expression level; phospholipid hydroperoxide glutathione peroxidase; dhodh protein; ferrostatin 1; gas41 protein; gclc protein; nqo1 protein; rebemadlin; slc7a11 protein; yeats4 protein; a-375 cell line; antioxidant responsive element; nrf2 signaling; transactivation assay |
| Journal Title: | Nature Communications |
| Volume: | 15 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-01-01 |
| Start Page: | 2531 |
| Language: | English |
| DOI: | 10.1038/s41467-024-46857-w |
| PUBMED: | 38514704 |
| PROVIDER: | scopus |
| PMCID: | PMC10957913 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
