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Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by T

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Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by T cancers Article 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) Oluwaseun Adebayo Bamodu 1,2,3 , Yuan-Hung Wang 2,4, Chen-Hsun Ho 5,6, Su-Wei Hu 1,4,7, Chia-Da Lin 1,7, Kai-Yi Tzou 1,7,8, Wen-Ling Wu 1,7, Kuan-Chou Chen 1,4,7,8 and Chia-Chang Wu 1,7,8,* 1 Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan; [email protected] (O.A.B.); [email protected] (S.-W.H.); [email protected] (C.-D.L.); [email protected] (K.-Y.T.); [email protected] (W.-L.W.); [email protected] (K.-C.C.) 2 Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan; [email protected] 3 Department of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan 4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan 5 Department of Surgery, Division of Urology, Shin Kong Wu Ho-Su Memorial Hospital, Citation: Bamodu, O.A.; Wang, Y.-H.; Taipei City 111, Taiwan; [email protected] Ho, C.-H.; Hu, S.-W.; Lin, C.-D.; Tzou, 6 School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City 242, Taiwan K.-Y.; Wu, W.-L.; Chen, K.-C.; Wu, 7 TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei City 110, Taiwan 8 C.-C. Genetic Suppressor Element 1 Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, (GSE1) Promotes the Oncogenic and Taipei City 110, Taiwan Recurrent Phenotypes of * Correspondence: [email protected] or [email protected]; Tel./Fax: +886-02-22490088 (ext. 8111) Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Simple Summary: In urological oncology clinics, worldwide, castration resistance and metastasis Calcium Signal Transducer 2 constitute a clinical quagmire and continue to hinder treatment success, despite the diagnostic and (TACSTD2). Cancers 2021, 13, 3959. therapeutic advances of the last three decades. In this study, we present data that provide some https://doi.org/10.3390/ preclinical evidence of the oncogenic role of dysregulated GSE1-TACSTD2 signaling, and show that cancers13163959 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 Academic Editor: Zakaria Y. metastatic-recurrent phenotypes of patients with prostate cancer. Abd Elmageed Abstract: Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and Received: 3 July 2021 mortality. Castration resistance and metastasis are clinical challenges and continue to impede Accepted: 3 August 2021 Published: 5 August 2021 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 Publisher’s Note: MDPI stays neutral resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. with regard to jurisdictional claims in Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy published maps and institutional affil- resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi- iations. 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 Copyright: © 2021 by the authors. direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, Licensee MDPI, Basel, Switzerland. castration resistance, and disease progression and modulates the clinical and immune statuses of This article is an open access article patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and distributed under the terms and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the conditions of the Creative Commons GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in Attribution (CC BY) license (https:// patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate creativecommons.org/licenses/by/ that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and 4.0/). Cancers 2021, 13, 3959. https://doi.org/10.3390/cancers13163959 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3959 2 of 24 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. Keywords: prostate cancer; GSE1; TACSTD2; advanced disease; CRPC; castration resistance; therapy resistance; abiraterone; enzalutamide 1. Introduction Prostate cancer (PCa; International Classification of Diseases, ICD: C61) remains a prin- cipal cause of cancer-related morbidity and mortality. Globally, 1,414,259 newly diagnosed cases and 375,304 PCa-specific deaths were reported in the year 2020 alone, with a projected 1.72-fold increase in incidence and 1.97-fold increase in mortality worldwide by the year 2040 [1]. This may be associated with enhanced androgenic signaling, ensuing castration resistance and metastasis, a triad that continues to pose a significant challenge in urology clinics, especially impeding therapeutic success in spite of diagnostic and therapeutic advances [2–4]. Current data indicate that at least one in every three PCa cases will acquire a metastatic and/or recurrent phenotype within 48 months of the initial diagnosis [2,3]. One-fifth of these patients, with metastatic or recurrent disease, subsequently progress to castration-resistant PCa (CRPC) by the fifth year of clinical follow-up [2,3]. Unfortunately, after the development of castration resistance, the approximate median survival is a dismal 14 months [2,3]. Cumulative evidence indicates that androgen signaling plays a critical role in the pathogenesis and progression of prostate cancer [4]. Typically, bio-cellular events that facilitate the viability, survival, and proliferation of cancerous prostate cells are regulated by the androgen receptor (AR) directly or through the modulation of molecular mediators and downstream effectors [5]. Thus, the mainstay of treatment for metastatic PCa remains androgen-deprivation therapy (ADT), which inhibits AR activity, suppresses AR target genes, and elicits clinical remission that will last a couple of years [4,5]. However, because of the non-curative nature of ADT, progression to CRPC often follows, largely secondary to reactivated/restored androgen signaling [4,5]. To address this biological phenomenon, second-generation AR inhibitors (ARIs), such as abiraterone and enzalutamide, were developed to further suppress residual AR signaling and are the treatments of choice for patients with CRPC [6,7]. However, the clinical conundrum lingers, with a lack of durable complete remission (CR) and eventual treatment failure, despite an initial response and the promise of extended survival [6,7]. The early identification of patients at high risk of metastasis and/or recurrence after initial treatment may benefit clinical decision making and aid in the development of an effective treatment strategy that can improve prognosis. Over the past two decades, there has been an increase in biomarker exploration in the field of genitourinary oncology, with piqued interest in the molecular mechanisms underlying the roles of these biomarkers in oncogenicity, metabolic reprogramming, disease progression, and responses to therapy in patients with PCa [4,5]. This molecular renaissance, hinged on the discovery and validation of novel diagnostic or prognostic biomarkers, continues to facilitate the elucidation of the pathogenesis and biology of PCa and concomitantly facilitates patient stratification into responders or non-responders to certain therapies, as well as discriminating ‘progres- sors’ from ‘non-progressors’ [4–7]. Against the background of the unabated incidence, high mortality burden, and increased odds of disease progression, as well as a largely Cancers 2021, 13, 3959 3 of 24 unclear underlying bio-mechanism of progression, the present study probed actionable biomarkers that could provide clinically objective measures of PCa biology, improve patient stratification, and inform therapeutic decision making. Recently, it was reported that the relatively unknown genetic suppressor element 1 (GSE1, KIAA0182), a proline-rich protein with
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