Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R.China.
Department of Medicine, Hematology-Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachussetts, USA.
Prostate. 2023 Nov;83(15):1415-1429. doi: 10.1002/pros.24603. Epub 2023 Aug 11.
The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region.
RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites.
In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site.
Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.
雄激素受体（AR）具有反式转录抑制作用的发现，使其作为典型的转录因子的功能趋于完整，其内在的激活和抑制功能与共因子的竞争和再分配有关。事实上，AR 的双重功能在致癌 8q24-MYC 区域的全基因座调节中得到了例证。
采用 RT-qPCR 检测和公共 RNA 谱数据集来评估雄激素敏感细胞系中 MYC 的转录。计算公共 ChIP-seq 和 RNA-Seq 数据集，以评估 AR-MYC 的直接和间接特征。监测典型的 MYC 和 AR 通路中的基因集，以验证它们的相互作用。在 AR 基因座中进行生物信息学和染色体构象捕获（3C）检测，以检查雄激素诱导的远端调节。最后，在 AR 和 MYC 结合位点之间全面跟踪共因子的再分布。
在本报告中，我们发现 MYC 对雄激素的反应呈超敏性，与 AR 作为天然雄激素效应物的自然功能相抗衡。此外，AR 和 MYC 的直接和间接转录程序都在积极平衡。通过建立雄激素介导的与 MYC 介导的基因子集，我们验证了 AR 和 MYC 通路都是双向的，并且广泛交织。此外，我们确定 AR 基因座类似于 MYC 基因区域，并且通过表观遗传学和染色质结构改变，两个基因座都被雄激素抑制。重要的是，沿着前列腺癌（PCa）基因组的转录因子分析表明，PCa 转录组在 AR 结合位点和 MYC 结合位点之间动态平衡。
总的来说，我们的研究结果分层了 AR-MYC 相互作用，这些相互作用广泛连接且组织复杂，以补偿关键的 PCa 转录程序并中和过度的信号传导。
