Department of Urology, Nihon University School of Medicine, 30-1, Ooyaguchikamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, VIC, 3800, Australia.
BMC Cancer. 2024 May 2;24(1):554. doi: 10.1186/s12885-024-12298-3.
Prostate cancer is dependent on androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) has proven effective in targeting prostate cancer. However, castration-resistant prostate cancer (CRPC) eventually emerges. AR signaling inhibitors (ARSI) have been also used, but resistance to these agents develops due to genetic AR alterations and epigenetic dysregulation.
In this study, we investigated the role of OCT1, a member of the OCT family, in an AR-positive CRPC patient-derived xenograft established from a patient with resistance to ARSI and chemotherapy. We conducted a genome-wide analysis chromatin immunoprecipitation followed by sequencing and bioinformatic analyses using public database.
Genome-wide analysis of OCT1 target genes in PDX 201.1 A revealed distinct OCT1 binding sites compared to treatment-naïve cells. Bioinformatic analyses revealed that OCT1-regulated genes were associated with cell migration and immune system regulation. In particular, C-terminal Binding Protein 2 (CTBP2), an OCT1/AR target gene, was correlated with poor prognosis and immunosuppressive effects in the tumor microenvironment. Metascape revealed that CTBP2 knockdown affects genes related to the immune response to bacteria. Furthermore, TISIDB analysis suggested the relationship between CTBP2 expression and immune cell infiltration in prostate cancer, suggesting that it may contribute to immune evasion in CRPC.
Our findings shed light on the genome-wide network of OCT1 and AR in AR-positive CRPC and highlight the potential role of CTBP2 in immune response and tumor progression. Targeting CTBP2 may represent a promising therapeutic approach for aggressive AR-positive CRPC. Further validation will be required to explore novel therapeutic strategies for CRPC management.
前列腺癌依赖于雄激素受体（AR）信号，雄激素剥夺疗法（ADT）已被证明对前列腺癌具有靶向作用。然而，去势抵抗性前列腺癌（CRPC）最终还是会出现。AR 信号抑制剂（ARSI）也已被应用，但由于遗传 AR 改变和表观遗传失调，这些药物会产生耐药性。
在这项研究中，我们研究了 OCT1 在一位对 ARSI 和化疗耐药的 CRPC 患者来源的异种移植模型中的作用，该模型源自一位对 ARSI 和化疗耐药的患者。我们进行了全基因组分析，使用公共数据库进行了染色质免疫沉淀测序和生物信息学分析。
PDX201.1A 中 OCT1 靶基因的全基因组分析显示，与治疗前的细胞相比，OCT1 结合位点存在明显差异。生物信息学分析表明，OCT1 调控的基因与细胞迁移和免疫系统调节有关。特别是 OCT1/AR 靶基因 C 端结合蛋白 2（CTBP2）与肿瘤微环境中的不良预后和免疫抑制作用相关。Metascape 分析表明，CTBP2 敲低会影响与细菌免疫反应相关的基因。此外，TISIDB 分析表明 CTBP2 表达与前列腺癌中免疫细胞浸润有关，提示其可能有助于 CRPC 的免疫逃避。
我们的研究结果揭示了 OCT1 和 AR 在 AR 阳性 CRPC 中的全基因组网络，并强调了 CTBP2 在免疫反应和肿瘤进展中的潜在作用。靶向 CTBP2 可能为侵袭性 AR 阳性 CRPC 提供一种有前途的治疗方法。需要进一步验证以探索 CRPC 管理的新治疗策略。
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