Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression
<i>TP53</i> is the most common mutated gene in human cancer. Mutant p53 protein loses its tumor-suppressor properties and gains oncogenic activity. Mutant p53 is a therapeutic target in a broad range of cancer types. However, how mutant p53 is epigenetically regulated during tumor progre...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/15163 |
| _version_ | 1797463035368964096 |
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| author | Julie Xia Zhou Ewud Agborbesong Linda Xiaoyan Li Xiaogang Li |
| author_facet | Julie Xia Zhou Ewud Agborbesong Linda Xiaoyan Li Xiaogang Li |
| author_sort | Julie Xia Zhou |
| collection | DOAJ |
| description | <i>TP53</i> is the most common mutated gene in human cancer. Mutant p53 protein loses its tumor-suppressor properties and gains oncogenic activity. Mutant p53 is a therapeutic target in a broad range of cancer types. However, how mutant p53 is epigenetically regulated during tumor progression remains elusive. In this study, we found that the upregulation of mutant p53 is mediated by bromodomain protein BRD4 in triple-negative breast cancer (TNBC) cells. Inhibition of BRD4 with its inhibitor JQ1 or knockdown of BRD4 suppressed the transcription of mutant p53, which led to the re-expression of p21, the inhibition of S-phase entry, and colony formation in TNBC cells. BRD4 also positively regulated the transcription of wild-type p53, whereas JQ1 treatment and knockdown of BRD4 decreased the expression of p21 in MCF-7 cells. Knockdown of BRD4 resulted in attenuation of TNBC tumor growth in vivo. Taken together, our results uncover a novel regulatory mechanism of mutant p53 via BRD4, and suggest that the bromodomain inhibitor suppresses tumorigenesis through targeting mutant p53 in TNBC. |
| first_indexed | 2024-03-09T17:45:56Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:45:56Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e01e669205344b95bcc73cb990ab29a72023-11-24T11:14:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123231516310.3390/ijms232315163Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC ProgressionJulie Xia Zhou0Ewud Agborbesong1Linda Xiaoyan Li2Xiaogang Li3Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA <i>TP53</i> is the most common mutated gene in human cancer. Mutant p53 protein loses its tumor-suppressor properties and gains oncogenic activity. Mutant p53 is a therapeutic target in a broad range of cancer types. However, how mutant p53 is epigenetically regulated during tumor progression remains elusive. In this study, we found that the upregulation of mutant p53 is mediated by bromodomain protein BRD4 in triple-negative breast cancer (TNBC) cells. Inhibition of BRD4 with its inhibitor JQ1 or knockdown of BRD4 suppressed the transcription of mutant p53, which led to the re-expression of p21, the inhibition of S-phase entry, and colony formation in TNBC cells. BRD4 also positively regulated the transcription of wild-type p53, whereas JQ1 treatment and knockdown of BRD4 decreased the expression of p21 in MCF-7 cells. Knockdown of BRD4 resulted in attenuation of TNBC tumor growth in vivo. Taken together, our results uncover a novel regulatory mechanism of mutant p53 via BRD4, and suggest that the bromodomain inhibitor suppresses tumorigenesis through targeting mutant p53 in TNBC.https://www.mdpi.com/1422-0067/23/23/15163BRD4p53triple-negative breast cancer |
| spellingShingle | Julie Xia Zhou Ewud Agborbesong Linda Xiaoyan Li Xiaogang Li Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression International Journal of Molecular Sciences BRD4 p53 triple-negative breast cancer |
| title | Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression |
| title_full | Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression |
| title_fullStr | Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression |
| title_full_unstemmed | Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression |
| title_short | Bromodomain Protein BRD4-Mediated Mutant p53 Transcription Promotes TNBC Progression |
| title_sort | bromodomain protein brd4 mediated mutant p53 transcription promotes tnbc progression |
| topic | BRD4 p53 triple-negative breast cancer |
| url | https://www.mdpi.com/1422-0067/23/23/15163 |
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