Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells
Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely un...
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MDPI AG
2024-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/2/905 |
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| author | Qiwei Yang Somayeh Vafaei Ali Falahati Azad Khosh Maria Victoria Bariani Mervat M. Omran Tao Bai Hiba Siblini Mohamed Ali Chuan He Thomas G. Boyer Ayman Al-Hendy |
| author_facet | Qiwei Yang Somayeh Vafaei Ali Falahati Azad Khosh Maria Victoria Bariani Mervat M. Omran Tao Bai Hiba Siblini Mohamed Ali Chuan He Thomas G. Boyer Ayman Al-Hendy |
| author_sort | Qiwei Yang |
| collection | DOAJ |
| description | Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age. |
| first_indexed | 2024-03-08T09:54:03Z |
| format | Article |
| id | doaj.art-9eeca701841d46a9b58604e2a27340d4 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T09:54:03Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9eeca701841d46a9b58604e2a27340d42024-01-29T13:55:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-0125290510.3390/ijms25020905Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid CellsQiwei Yang0Somayeh Vafaei1Ali Falahati2Azad Khosh3Maria Victoria Bariani4Mervat M. Omran5Tao Bai6Hiba Siblini7Mohamed Ali8Chuan He9Thomas G. Boyer10Ayman Al-Hendy11Department of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USADepartment of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USADNA GTx LAB, Dubai Healthcare City, Dubai 505262, United Arab EmiratesDepartment of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USADepartment of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USAObstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USADepartment of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USADepartment of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USADepartment of Chemistry, University of Chicago, Chicago, IL 60637, USADepartment of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Obstetrics and Gynecology, University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USABromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.https://www.mdpi.com/1422-0067/25/2/905uterine leiomyomaBRD9I-BRD9cell proliferationapoptosisextracellular matrix |
| spellingShingle | Qiwei Yang Somayeh Vafaei Ali Falahati Azad Khosh Maria Victoria Bariani Mervat M. Omran Tao Bai Hiba Siblini Mohamed Ali Chuan He Thomas G. Boyer Ayman Al-Hendy Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells International Journal of Molecular Sciences uterine leiomyoma BRD9 I-BRD9 cell proliferation apoptosis extracellular matrix |
| title | Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells |
| title_full | Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells |
| title_fullStr | Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells |
| title_full_unstemmed | Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells |
| title_short | Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells |
| title_sort | bromodomain containing protein 9 regulates signaling pathways and reprograms the epigenome in immortalized human uterine fibroid cells |
| topic | uterine leiomyoma BRD9 I-BRD9 cell proliferation apoptosis extracellular matrix |
| url | https://www.mdpi.com/1422-0067/25/2/905 |
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