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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)

SIMPLE SUMMARY: In urological oncology clinics, worldwide, castration resistance and metastasis constitute a clinical quagmire and continue to hinder treatment success, despite the diagnostic and therapeutic advances of the last three decades. In this study, we present data that provide some preclin...

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Autores principales: Bamodu, Oluwaseun Adebayo, Wang, Yuan-Hung, Ho, Chen-Hsun, Hu, Su-Wei, Lin, Chia-Da, Tzou, Kai-Yi, Wu, Wen-Ling, Chen, Kuan-Chou, Wu, Chia-Chang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392851/
https://www.ncbi.nlm.nih.gov/pubmed/34439112
http://dx.doi.org/10.3390/cancers13163959
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author Bamodu, Oluwaseun Adebayo
Wang, Yuan-Hung
Ho, Chen-Hsun
Hu, Su-Wei
Lin, Chia-Da
Tzou, Kai-Yi
Wu, Wen-Ling
Chen, Kuan-Chou
Wu, Chia-Chang
author_facet Bamodu, Oluwaseun Adebayo
Wang, Yuan-Hung
Ho, Chen-Hsun
Hu, Su-Wei
Lin, Chia-Da
Tzou, Kai-Yi
Wu, Wen-Ling
Chen, Kuan-Chou
Wu, Chia-Chang
author_sort Bamodu, Oluwaseun Adebayo
collection PubMed
description SIMPLE SUMMARY: In urological oncology clinics, worldwide, castration resistance and metastasis constitute a clinical quagmire and continue to hinder treatment success, despite the diagnostic and therapeutic advances of the last three decades. In this study, we present data that provide some preclinical evidence of the oncogenic role of dysregulated GSE1-TACSTD2 signaling, and show that the molecular or pharmacological targeting of GSE1 is a workable treatment strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing cancerous cells to treatment, and repressing the metastatic-recurrent phenotypes of patients with prostate cancer. ABSTRACT: 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(high)TACSTD2(low) expression are more prone to recurrence and disease-specific death than their GSE1(low)TACSTD2(high) 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.
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spelling pubmed-83928512021-08-28 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) Bamodu, Oluwaseun Adebayo Wang, Yuan-Hung Ho, Chen-Hsun Hu, Su-Wei Lin, Chia-Da Tzou, Kai-Yi Wu, Wen-Ling Chen, Kuan-Chou Wu, Chia-Chang Cancers (Basel) Article SIMPLE SUMMARY: In urological oncology clinics, worldwide, castration resistance and metastasis constitute a clinical quagmire and continue to hinder treatment success, despite the diagnostic and therapeutic advances of the last three decades. In this study, we present data that provide some preclinical evidence of the oncogenic role of dysregulated GSE1-TACSTD2 signaling, and show that the molecular or pharmacological targeting of GSE1 is a workable treatment strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing cancerous cells to treatment, and repressing the metastatic-recurrent phenotypes of patients with prostate cancer. ABSTRACT: 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(high)TACSTD2(low) expression are more prone to recurrence and disease-specific death than their GSE1(low)TACSTD2(high) 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. MDPI 2021-08-05 /pmc/articles/PMC8392851/ /pubmed/34439112 http://dx.doi.org/10.3390/cancers13163959 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bamodu, Oluwaseun Adebayo
Wang, Yuan-Hung
Ho, Chen-Hsun
Hu, Su-Wei
Lin, Chia-Da
Tzou, Kai-Yi
Wu, Wen-Ling
Chen, Kuan-Chou
Wu, Chia-Chang
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 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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392851/
https://www.ncbi.nlm.nih.gov/pubmed/34439112
http://dx.doi.org/10.3390/cancers13163959
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