ARv7 represses tumor suppressors genes in castration-resistant prostate cancer [ChIP-Seq]

Endocrine therapies in prostate cancer (PCa) treatment block androgen receptor (AR) function, but are palliative as tumors progress to a lethal, castration-resistant state (CRPC). CRPC remains dependent on AR signaling, which can act through the full-length AR (ARfl) or constitutively active splice variants, e.g. ARv7. We show here that both ARfl and ARv7 bind to the same genomic region and heterodimerize in a CRPC cell line model, but regulate distinct transcriptomes. ARv7, unlike ARfl, preferentially represses transcription and demonstrates an increased affinity for co-repressors, decreased chromatin residence time and lower dependence on FOXA1 binding. We identified a group of ARv7-repressed genes, including the UDP-galactosyltransferase B4GALT1 that are down-regulated during PCa progression and important for CRPC growth. In conclusion, we propose that ARv7 acts as a transcriptional repressor of genes that limit proliferation, a function that should be targeted in CRPC patients. ChIP-seq from shRNA-mediated knock-down experiments in prostate cancer cell lines

前列腺癌（prostate cancer, PCa）治疗中的内分泌疗法可阻断雄激素受体（androgen receptor, AR）的功能，但当肿瘤进展至致命性去势抵抗状态（castration-resistant state, CRPC）时，该疗法仅能发挥姑息治疗作用。CRPC仍依赖AR信号通路，该通路可通过全长AR（full-length AR, ARfl）或组成型激活剪接变体（如ARv7）介导信号传导。本研究结果显示，在CRPC细胞系模型中，ARfl与ARv7可结合于同一基因组区域并发生异二聚化，但二者调控的转录组存在显著差异。与ARfl不同，ARv7优先介导转录抑制，且对共抑制因子的亲和力增强、染色质驻留时间缩短，同时对FOXA1结合的依赖性降低。本研究鉴定出一组受ARv7抑制的基因，其中包括UDP-半乳糖基转移酶B4GALT1，该类基因在PCa进展过程中表达下调，且对CRPC的生长至关重要。综上，我们提出ARv7可作为抑制细胞增殖基因的转录抑制因子，这一功能可作为CRPC患者的潜在治疗靶点。本研究的染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）数据来自前列腺癌细胞系中短发夹RNA（short hairpin RNA, shRNA）介导的基因敲减实验。