Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)
Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genet...
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MDPI AG
2021-08-01
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| Online Access: | https://www.mdpi.com/2072-6694/13/16/3959 |
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| author | Oluwaseun Adebayo Bamodu Yuan-Hung Wang Chen-Hsun Ho Su-Wei Hu Chia-Da Lin Kai-Yi Tzou Wen-Ling Wu Kuan-Chou Chen Chia-Chang Wu |
| author_facet | Oluwaseun Adebayo Bamodu Yuan-Hung Wang Chen-Hsun Ho Su-Wei Hu Chia-Da Lin Kai-Yi Tzou Wen-Ling Wu Kuan-Chou Chen Chia-Chang Wu |
| author_sort | Oluwaseun Adebayo Bamodu |
| collection | DOAJ |
| description | Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1<sup>high</sup>TACSTD2<sup>low</sup> expression are more prone to recurrence and disease-specific death than their GSE1<sup>low</sup>TACSTD2<sup>high</sup> counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa. |
| first_indexed | 2024-03-10T08:57:21Z |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:57:21Z |
| publishDate | 2021-08-01 |
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| series | Cancers |
| spelling | doaj.art-434b04a282e042a3a81dff60b316d4fd2023-11-22T07:01:40ZengMDPI AGCancers2072-66942021-08-011316395910.3390/cancers13163959Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)Oluwaseun Adebayo Bamodu0Yuan-Hung Wang1Chen-Hsun Ho2Su-Wei Hu3Chia-Da Lin4Kai-Yi Tzou5Wen-Ling Wu6Kuan-Chou Chen7Chia-Chang Wu8Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanDepartment of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanDepartment of Surgery, Division of Urology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei City 111, TaiwanDepartment of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanDepartment of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanDepartment of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanDepartment of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanDepartment of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanDepartment of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, TaiwanBackground: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1<sup>high</sup>TACSTD2<sup>low</sup> expression are more prone to recurrence and disease-specific death than their GSE1<sup>low</sup>TACSTD2<sup>high</sup> counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.https://www.mdpi.com/2072-6694/13/16/3959prostate cancerGSE1TACSTD2advanced diseaseCRPCcastration resistance |
| spellingShingle | Oluwaseun Adebayo Bamodu Yuan-Hung Wang Chen-Hsun Ho Su-Wei Hu Chia-Da Lin Kai-Yi Tzou Wen-Ling Wu Kuan-Chou Chen Chia-Chang Wu Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) Cancers prostate cancer GSE1 TACSTD2 advanced disease CRPC castration resistance |
| title | Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) |
| title_full | Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) |
| title_fullStr | Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) |
| title_full_unstemmed | Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) |
| title_short | Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) |
| title_sort | genetic suppressor element 1 gse1 promotes the oncogenic and recurrent phenotypes of castration resistant prostate cancer by targeting tumor associated calcium signal transducer 2 tacstd2 |
| topic | prostate cancer GSE1 TACSTD2 advanced disease CRPC castration resistance |
| url | https://www.mdpi.com/2072-6694/13/16/3959 |
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