Sharma Naomi L, Massie Charlie E, Butter Falk, Mann Matthias, Bon Helene, Ramos-Montoya Antonio, Menon Suraj, Stark Rory, Lamb Alastair D, Scott Helen E, Warren Anne Y, Neal David E, Mills Ian G
Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK Department of Urology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
Uro-oncology Research Group, CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Nucleic Acids Res. 2014 Jun;42(10):6256-69. doi: 10.1093/nar/gku281. Epub 2014 Apr 21.
In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention.
在前列腺癌（PC）中，雄激素受体（AR）在所有疾病阶段都是关键转录因子，包括去势抵抗性前列腺癌（CRPC）的晚期阶段。在本研究中，我们发现GABPα（一种在PC中上调的ETS因子）是一种与AR相互作用的转录因子。GABPα的表达使PC细胞系能够获得CRPC组织的一些分子和细胞特征以及更具侵袭性的生长表型。GABPα具有转录作用，可剖析PC中两种最常见的ETS基因融合的重叠顺反子组：与ETV1显著重叠，但与ERG靶基因不重叠。GABPα主要与基因启动子结合，调节三分之一的AR靶基因的表达，并在激素反应性和去势抵抗性PC模型中调节对AR拮抗剂的敏感性。本研究支持GABPα在CRPC中的关键作用，并揭示了治疗干预的潜在靶点。
