Scaravilli Mauro, Koivukoski Sonja, Latonen Leena
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Front Cell Dev Biol. 2021 Feb 9;9:623809. doi: 10.3389/fcell.2021.623809. eCollection 2021.
Androgens are steroid hormones governing the male reproductive development and function. As such, androgens and the key mediator of their effects, androgen receptor (AR), have a leading role in many diseases. Prostate cancer is a major disease where AR and its transcription factor function affect a significant number of patients worldwide. While disease-related AR-driven transcriptional programs are connected to the presence and activity of the receptor itself, also novel modes of transcriptional regulation by androgens are exploited by cancer cells. One of the most intriguing and ingenious mechanisms is to bring previously unconnected genes under the control of AR. Most often this occurs through genetic rearrangements resulting in fusion genes where an androgen-regulated promoter area is combined to a protein-coding area of a previously androgen-unaffected gene. These gene fusions are distinctly frequent in prostate cancer compared to other common solid tumors, a phenomenon still requiring an explanation. Interestingly, also another mode of connecting androgen regulation to a previously unaffected gene product exists via transcriptional read-through mechanisms. Furthermore, androgen regulation of fusion genes and transcripts is not linked to only protein-coding genes. Pseudogenes and non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) can also be affected by androgens and functions produced. In this review, we discuss the prevalence, molecular mechanisms, and functional evidence for androgen-regulated prostate cancer fusion genes and transcripts. We also discuss the clinical relevance of especially the most common prostate cancer fusion gene , as well as present open questions of prostate cancer fusions requiring further investigation.
雄激素是调控男性生殖发育和功能的类固醇激素。因此，雄激素及其作用的关键介质雄激素受体（AR）在许多疾病中起主导作用。前列腺癌是一种主要疾病，其中AR及其转录因子功能影响着全球大量患者。虽然与疾病相关的AR驱动的转录程序与受体本身的存在和活性有关，但癌细胞也利用了雄激素转录调控的新模式。最引人入胜且巧妙的机制之一是使以前未关联的基因受AR控制。这通常是通过基因重排导致融合基因产生，其中雄激素调节的启动子区域与以前不受雄激素影响的基因的蛋白质编码区域相结合。与其他常见实体瘤相比，这些基因融合在前列腺癌中明显更为频繁，这一现象仍有待解释。有趣的是，还存在另一种通过转录通读机制将雄激素调节与以前未受影响的基因产物联系起来的模式。此外，融合基因和转录本的雄激素调节不仅与蛋白质编码基因有关。假基因和非编码RNA（ncRNA），包括长链非编码RNA（lncRNA）也可受雄激素影响并产生功能。在本综述中，我们讨论了雄激素调节的前列腺癌融合基因和转录本的普遍性、分子机制和功能证据。我们还讨论了尤其是最常见的前列腺癌融合基因的临床相关性，以及提出了前列腺癌融合基因需要进一步研究的开放性问题。
