The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis
Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergen...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/21/5516 |
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| author | Lawrence David Mason Suresh Chava Kiran Kumar Reddi Romi Gupta |
| author_facet | Lawrence David Mason Suresh Chava Kiran Kumar Reddi Romi Gupta |
| author_sort | Lawrence David Mason |
| collection | DOAJ |
| description | Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy. |
| first_indexed | 2024-03-10T06:05:08Z |
| format | Article |
| id | doaj.art-f816bc3dd434425bb9f56253d5058512 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:05:08Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-f816bc3dd434425bb9f56253d50585122023-11-22T20:36:24ZengMDPI AGCancers2072-66942021-11-011321551610.3390/cancers13215516The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing ApoptosisLawrence David Mason0Suresh Chava1Kiran Kumar Reddi2Romi Gupta3Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35322, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35322, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35322, USADepartment of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35322, USAMelanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.https://www.mdpi.com/2072-6694/13/21/5516melanomaepigenetic regulatorsextracellular matrixbromodomainchromatin |
| spellingShingle | Lawrence David Mason Suresh Chava Kiran Kumar Reddi Romi Gupta The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis Cancers melanoma epigenetic regulators extracellular matrix bromodomain chromatin |
| title | The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis |
| title_full | The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis |
| title_fullStr | The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis |
| title_full_unstemmed | The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis |
| title_short | The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis |
| title_sort | brd9 7 inhibitor tp 472 blocks melanoma tumor growth by suppressing ecm mediated oncogenic signaling and inducing apoptosis |
| topic | melanoma epigenetic regulators extracellular matrix bromodomain chromatin |
| url | https://www.mdpi.com/2072-6694/13/21/5516 |
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