Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells
Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epitheliu...
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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/16/2046 |
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| author | Evelyn S. Sanchez-Hernandez Pedro T. Ochoa Tise Suzuki Greisha L. Ortiz-Hernandez Juli J. Unternaehrer Hossam R. Alkashgari Carlos J. Diaz Osterman Shannalee R. Martinez Zhong Chen Isaac Kremsky Charles Wang Carlos A. Casiano |
| author_facet | Evelyn S. Sanchez-Hernandez Pedro T. Ochoa Tise Suzuki Greisha L. Ortiz-Hernandez Juli J. Unternaehrer Hossam R. Alkashgari Carlos J. Diaz Osterman Shannalee R. Martinez Zhong Chen Isaac Kremsky Charles Wang Carlos A. Casiano |
| author_sort | Evelyn S. Sanchez-Hernandez |
| collection | DOAJ |
| description | Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR–LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein–protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR–LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa. |
| first_indexed | 2024-03-11T00:03:28Z |
| format | Article |
| id | doaj.art-8a09a807b0f94dcd8d1978ddc5ef6b3e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T00:03:28Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-8a09a807b0f94dcd8d1978ddc5ef6b3e2023-11-19T00:36:37ZengMDPI AGCells2073-44092023-08-011216204610.3390/cells12162046Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer CellsEvelyn S. Sanchez-Hernandez0Pedro T. Ochoa1Tise Suzuki2Greisha L. Ortiz-Hernandez3Juli J. Unternaehrer4Hossam R. Alkashgari5Carlos J. Diaz Osterman6Shannalee R. Martinez7Zhong Chen8Isaac Kremsky9Charles Wang10Carlos A. Casiano11Center for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USACenter for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USACenter for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USACenter for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USACenter for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USACenter for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADepartment of Basic Sciences, Ponce Health Sciences University, Ponce, PR 00716, USADepartment of Basic Sciences, Ponce Health Sciences University, Ponce, PR 00716, USADepartment of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADepartment of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USADepartment of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USACenter for Health Disparities and Molecular Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USAPatients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR–LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein–protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR–LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa.https://www.mdpi.com/2073-4409/12/16/2046autoantibodieschemoresistancedocetaxelexicorilantglucocorticoid receptorLEDGF/p75 |
| spellingShingle | Evelyn S. Sanchez-Hernandez Pedro T. Ochoa Tise Suzuki Greisha L. Ortiz-Hernandez Juli J. Unternaehrer Hossam R. Alkashgari Carlos J. Diaz Osterman Shannalee R. Martinez Zhong Chen Isaac Kremsky Charles Wang Carlos A. Casiano Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells Cells autoantibodies chemoresistance docetaxel exicorilant glucocorticoid receptor LEDGF/p75 |
| title | Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells |
| title_full | Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells |
| title_fullStr | Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells |
| title_full_unstemmed | Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells |
| title_short | Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells |
| title_sort | glucocorticoid receptor regulates and interacts with ledgf p75 to promote docetaxel resistance in prostate cancer cells |
| topic | autoantibodies chemoresistance docetaxel exicorilant glucocorticoid receptor LEDGF/p75 |
| url | https://www.mdpi.com/2073-4409/12/16/2046 |
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