Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53
Abstract The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07337-1 |
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| author | Yidan Wang Todd G. Kroll Linhui Hao Zhi Wen |
| author_facet | Yidan Wang Todd G. Kroll Linhui Hao Zhi Wen |
| author_sort | Yidan Wang |
| collection | DOAJ |
| description | Abstract The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis. Specifically, we identify a cancer-associated NR2E3R97H mutation, which not only fails to activate p53 but also impedes NR2E3WT-mediated p53 acetylation. Moreover, we show that the small-molecule agonist of NR2E3, 11a, penetrates tumor mass of uterine cancer patients and increases p53 activation. Additionally, both NR2E3 and 11a exhibit similar multifaceted anti-cancer properties, underscoring NR2E3 as a novel molecular vulnerability in cancer cells. We further explore drug repurposing screens of FDA-approved anti-cancer drugs to develop NR2E3-targeted combinatorial treatments, such as the 11a-Romidepsin combination in HeLa cells. The underlying molecular mechanisms of these drug synergies include the activation of p53 pathway and inhibition of oncogenic pathway like MYC. Overall, our findings suggest that NR2E3 holds promise as a therapeutic target for cancer treatment, offering new avenues for effective anti-cancer strategies. |
| format | Article |
| id | doaj-art-d72eb6915c224a19a4272475f1ec496f |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-d72eb6915c224a19a4272475f1ec496f2025-01-19T12:40:51ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111310.1038/s41419-025-07337-1Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53Yidan Wang0Todd G. Kroll1Linhui Hao2Zhi Wen3McArdle Laboratory for Cancer Research, University of Wisconsin-MadisonDepartment of Pathology, Marshfield Medical Center, Marshfield Clinic Health SystemInstitute of Molecular Virology, University of Wisconsin-MadisonCenter for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield Clinic Health SystemAbstract The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis. Specifically, we identify a cancer-associated NR2E3R97H mutation, which not only fails to activate p53 but also impedes NR2E3WT-mediated p53 acetylation. Moreover, we show that the small-molecule agonist of NR2E3, 11a, penetrates tumor mass of uterine cancer patients and increases p53 activation. Additionally, both NR2E3 and 11a exhibit similar multifaceted anti-cancer properties, underscoring NR2E3 as a novel molecular vulnerability in cancer cells. We further explore drug repurposing screens of FDA-approved anti-cancer drugs to develop NR2E3-targeted combinatorial treatments, such as the 11a-Romidepsin combination in HeLa cells. The underlying molecular mechanisms of these drug synergies include the activation of p53 pathway and inhibition of oncogenic pathway like MYC. Overall, our findings suggest that NR2E3 holds promise as a therapeutic target for cancer treatment, offering new avenues for effective anti-cancer strategies.https://doi.org/10.1038/s41419-025-07337-1 |
| spellingShingle | Yidan Wang Todd G. Kroll Linhui Hao Zhi Wen Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53 Cell Death and Disease |
| title | Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53 |
| title_full | Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53 |
| title_fullStr | Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53 |
| title_full_unstemmed | Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53 |
| title_short | Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53 |
| title_sort | orphan nuclear receptor nr2e3 is a new molecular vulnerability in solid tumors by activating p53 |
| url | https://doi.org/10.1038/s41419-025-07337-1 |
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