PDF(Pubmed)
Abstract：
Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal tail of AR and increases its association with the pioneer factor FOXA1. Consequently, AR binds to a distinct set of genomic loci enriched with FOXA1- and HOXB13-binding motifs to drive different transcriptional programs including an olfactory transduction pathway. Through the surprising upregulation of olfactory receptor gene transcription, TRAF4 increases intracellular cAMP levels and boosts E2F transcription factor activity to promote cell proliferation under androgen deprivation conditions. Altogether, these findings reveal a posttranslational mechanism driving AR-regulated transcriptional reprogramming to provide survival advantages for prostate cancer cells under castration conditions.
摘要：
去势抵抗性前列腺癌（CRPC）提出了主要的临床挑战，雄激素受体（AR）仍然是关键的致癌参与者。若干证据表明,在CRPC中,AR在雄激素剥夺后诱导不同的转录程序。然而,引发AR与CRPC中一组不同基因组位点结合的机制以及它如何促进CRPC发育仍不清楚.我们在此证明，由E3泛素连接酶TRAF4介导的AR的非典型泛素化在此过程中起重要作用。TRAF4在CRPC中高度表达并促进CRPC的发展。它在AR的C末端尾部介导K27连接的泛素化，并增加其与先驱因子FOXA1的关联。因此,AR结合富含FOXA1-和HOXB13结合基序的一组不同的基因组基因座,以驱动不同的转录程序,包括嗅觉转导途径。通过令人惊讶的嗅觉受体基因转录上调，TRAF4增加细胞内cAMP水平并增强E2F转录因子活性以促进雄激素剥夺条件下的细胞增殖。总之,这些发现揭示了翻译后机制驱动AR调节的转录重编程,从而为去势条件下的前列腺癌细胞提供存活优势.
