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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Akira Yokomizo Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Seiji Naito Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Oxidative stress caused by an increase in reactive oxygen species levels or a decrease in cellular antioxidant capacity can evoke the modulation of various cellular events including androgen receptor (AR) signaling via direct or indirect interactions. In this review, we summarize the mechanisms of AR activation by oxidative stress including: i) AR overexpression; ii) AR activation by AR co-regulators or intracellular signal transduction pathways; iii) generation of AR mutations or splice variants; and iv) de novo androgen synthesis. AR signaling augmented by oxidative stress appears to contribute to pro-survival and anti-apoptotic effects in prostate cancer cells in response to androgen deprivation therapy. In addition, AR signaling suppresses anti-survival and pro-apoptotic effects in prostate cancer cells in response to various cytotoxic and tumor-suppressive interventions including taxanes and radiation through the modulation of βIII-tubulin and ataxia telangiectasia-mutated kinase expression respectively. Taken together, AR signaling appears to render prostate cancer cells refractory to various therapeutic interventions including castration, taxanes, and radiation, indicating that AR signaling is a comprehensive resistant factor and crucial target for prostate cancer treatment.

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Eiji Kashiwagi Departments of ce:sup loc="post">1Urology, Clinical Chemistry and Laboratory Medicine

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Masaki Shiota Departments of ce:sup loc="post">1Urology, Clinical Chemistry and Laboratory Medicine

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Akira Yokomizo Departments of ce:sup loc="post">1Urology, Clinical Chemistry and Laboratory Medicine

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Momoe Itsumi Departments of ce:sup loc="post">1Urology, Clinical Chemistry and Laboratory Medicine

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Junichi Inokuchi Departments of ce:sup loc="post">1Urology, Clinical Chemistry and Laboratory Medicine

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Takeshi Uchiumi Departments of ce:sup loc="post">1Urology, Clinical Chemistry and Laboratory Medicine

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Seiji Naito Departments of ce:sup loc="post">1Urology, Clinical Chemistry and Laboratory Medicine

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Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally, EP3 (PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer.

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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Shusuke Akamatsu Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Shigehiro Tsukahara Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Shohei Nagakawa Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takashi Matsumoto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Hormonal therapies including androgen deprivation therapy and androgen receptor (AR) pathway inhibitors such as abiraterone and enzalutamide have been widely used to treat advanced prostate cancer. However, treatment resistance emerges after hormonal manipulation in most prostate cancers, and it is attributable to a number of mechanisms, including AR amplification and overexpression, AR mutations, the expression of constitutively active AR variants, intra-tumor androgen synthesis, and promiscuous AR activation by other factors. Although various AR mutations have been reported in prostate cancer, specific AR mutations (L702H, W742L/C, H875Y, F877L, and T878A/S) were frequently identified after treatment resistance emerged. Intriguingly, these hot spot mutations were also revealed to change the binding affinity of ligands including steroids and antiandrogens and potentially result in altered responses to AR pathway inhibitors. Currently, precision medicine utilizing genetic and genomic data to choose suitable treatment for the patient is becoming to play an increasingly important role in clinical practice for prostate cancer management. Since clinical data between AR mutations and the efficacy of AR pathway inhibitors are accumulating, monitoring the AR mutation status is a promising approach for providing precision medicine in prostate cancer, which would be implemented through the development of clinically available testing modalities for AR mutations using liquid biopsy. However, there are few reviews on clinical significance of AR hot spot mutations in prostate cancer. Then, this review summarized the clinical landscape of AR mutations and discussed their potential implication for clinical utilization.

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Masaki Shiota Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Momoe Itsumi Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Ario Takeuchi Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Kenjiro Imada Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan
Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Akira Yokomizo Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Hidetoshi Kuruma Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Junichi Inokuchi Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Katsunori Tatsugami Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Takeshi Uchiumi Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Yoshinao Oda Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Seiji Naito Departments of Urology, Anatomic Pathology, Department of Urology, Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3‐1‐1 Maidashi, Higashi‐ku, Fukuoka 812‐8582, Japan

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Although invasive and metastatic progression via the epithelial-mesenchymal transition (EMT) and acquisition of resistance to castration are both critical steps in prostate cancer, the molecular mechanism of this interaction remains unclear. In this study, we aimed to elucidate the interaction of signaling between castration resistance and EMT, and to apply this information to the development of a novel therapeutic concept using transforming growth factor-β (TGF-β) inhibitor SB525334 combined with androgen-deprivation therapy against prostate cancer using an in vivo model. This study revealed that an EMT inducer (TGF-β) induced full-length androgen receptor (AR) and AR variant expression. In addition, a highly invasive clone showed augmented full-length AR and AR variant expression as well as acquisition of castration resistance. Conversely, full-length AR and AR as well as Twist1 and mesenchymal molecules variant expression were up-regulated in castration-resistant LNCaP xenograft. Finally, TGF-β inhibitor suppressed Twist1 and AR expression as well as prostate cancer growth combined with castration. Taken together, these results demonstrate that Twist1/AR signaling was augmented in castration resistant as well as mesenchymal-phenotype prostate cancer, indicating the molecular mechanism of mutual and functional crosstalk between EMT and castration resistance, which may play a crucial role in prostate carcinogenesis and progression.

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Masaki Shiota Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Ario Takeuchi Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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YooHyun Song Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Akira Yokomizo Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Eiji Kashiwagi Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Takeshi Uchiumi Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Kentaro Kuroiwa Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Katsunori Tatsugami Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Naohiro Fujimoto Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Yoshinao Oda Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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Seiji Naito Departments of, Urology, Anatomic Pathology, Clinical Chemistry and Laboratory Medicine, Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

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The androgen receptor (AR) is well known to play a central role in the pathogenesis of prostate cancer (PCa). In several studies, AR was overexpressed in castration-resistant PCa (CRPC). However, the mechanism of AR overexpression in CRPC is not fully elucidated. Y-box binding protein-1 (YB-1) is a pleiotropic transcription factor that is upregulated in CPRC. We aimed to elucidate the role of YB-1 in castration resistance of PCa and identify therapeutic potential of targeting YB-1. Using immunohistochemistry, we found that nuclear YB-1 expression significantly correlated with the Gleason score and AR expression in PCa tissues. In PCa cells, YB-1 regulated AR expression at the transcriptional level. Furthermore, YB-1 expression and nuclear localization were upregulated in CRPC cells. Overexpression of AR, as well as YB-1, conferred castration-resistant growth in LNCaP and 22Rv1 cells. Conversely, knocking down YB-1 resulted in suppressed cell growth and induced apoptosis, which was more efficient than knocking down AR in LNCaP cells. In other types of PCa cells, such as CRPC cells, knocking down YB-1 resulted in a significant reduction of cell growth. In conclusion, these findings suggested that YB-1 induces castration resistance in androgen-dependent PCa cells via AR expression. Thus, YB-1 may be a promising therapeutic target for PCa, as well as CRPC.

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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Akira Yokomizo Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Ario Takeuchi Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Eiji Kashiwagi Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takashi Dejima Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Junichi Inokuchi Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Katsunori Tatsugami Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takeshi Uchiumi Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that protein kinase C (PKC) activation followed by Twist1 and androgen receptor (AR) induction played a critical role in castration resistance, but the precise molecular mechanism remains unknown. This study aimed to elucidate the relevant molecular mechanism, focusing on NF-κB transcription factor. We examined the activity of NF-κB after PKC inhibition, and the expression of Twist1 and AR after inhibition of NF-κB in human prostate cancer cells. We also investigated the status of PKC/NF-κB after inhibition of AR signaling in cells resistant to hormonal therapy. As a result, inhibition of PKC signaling using knockdown and small-molecule inhibition of PKC suppressed RelA activity, while blocking NF-κB suppressed Twist1 and AR expression. Conversely, inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction. Finally, NF-κB was activated in both castration-resistant and enzalutamide-resistant cells. In conclusion, NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.

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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Satoshi Endo United Graduate School of Medical Information Sciences, Gifu University, Gifu, Japan
Center for One Medicine Innovative Translational Research (COMIT), Gifu University, Gifu, Japan

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Shigehiro Tsukahara Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Tokiyoshi Tanegashima Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Satoshi Kobayashi Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Takashi Matsumoto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3β-hydroxysteroid dehydrogenases (3βHSDs) play critical roles in extragonadal androgen synthesis, especially 3βHSD1. Increased expression of 3βHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3βHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3βHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and posttranscriptional modifications. Additionally, the clinical significance of HSD3B1 genotypes, particularly the rs1047303 variant, has been extensively studied. The impact of HSD3B1 genotypes on treatment outcomes varies according to the therapy administered, suggesting the potential of HSD3B1 genotyping for personalized medicine. Targeting 3βHSDs may be a promising strategy for prostate cancer management. Overall, understanding the roles of 3βHSDs and their genetic variations may enable the development and optimization of novel treatments for prostate cancer.

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Masaki Shiota Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Shuichi Tatarano Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

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Toshiyuki Kamoto Department of Urology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan

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Hideyasu Matsuyama Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, Japan

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Hideki Sakai Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

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Tsukasa Igawa Department of Urology, School of Medicine, Kurume University, Kurume, Japan

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Tomomi Kamba Department of Urology, Kumamoto University, Kumamoto, Japan

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Naohiro Fujimoto Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

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Yuya Sekine Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan

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Hiroko Kimura Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Shintaro Narita Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan

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Naoki Terada Department of Urology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan

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Yukihide Momozawa Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

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Shusuke Akamatsu Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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Tomonori Habuchi Department of Urology, Graduate School of Medicine, Akita University, Akita, Japan

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Akira Yokomizo Department of Urology, Harasanshin Hospital, Fukuoka, Japan

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Seiji Naito Department of Urology, Harasanshin Hospital, Fukuoka, Japan

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Masatoshi Eto Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

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Androgen-deprivation therapy (ADT) has been widely used for the treatment of advanced prostate cancer. However, prognosis and adverse events (AEs) vary among patients. This study aimed to identify genetic markers able to predict the outcome of ADT. Japanese patients treated with primary ADT for advanced prostate cancer in the KYUCOG-1401 trial were enrolled as a development set. A distinct population of advanced prostate cancer cases treated with ADT was included as a validation set. Single-nucleotide polymorphisms (SNPs) associated with radiographic progression-free survival (rPFS) at 1 year and AEs including de novo diabetes mellitus (DM), arthralgia, and de novo dyslipidemia were identified in the development set by a genome-wide association study (GWAS). The SNPs associated with rPFS in the development study were then genotyped in the validation set. GWAS followed by validation identified SNPs (rs76237622 in PRR27 and rs117573572 in MTAP) that were associated with overall survival (OS) in ADT. A genetic prognostic model using these SNPs showed excellent predictive efficacy for PFS and OS in ADT. In addition, GWAS showed that several SNPs were associated with de novo DM, arthralgia, and de novo dyslipidemia in ADT. This study identified novel multiple SNPs that correlated with outcomes in ADT. Future studies on correlations affecting the therapeutic efficacy of ADT-based combination therapies would make a valuable contribution to the development of personalized medicine.

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