Abstract
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 de novo 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 TMPRSS2-ERG, as well as present open questions of prostate cancer fusions requiring further investigation.
Highlights
Androgens are steroid hormones governing the development of male reproductive tract organs and secondary male sex characteristics, as well as functioning in the regulation of muscle mass, fat deposition, and function of steroid hormone-sensitive neurons (Werner and Holterhus, 2014)
The frequent gene fusions in prostate cancer are a curiosity amongst solid tumors
Despite a lot of effort, the field has yet to pinpoint why and how TMPRSS2-ERG fusion is an early event in prostate cancer development, yet the most significant functions of it seem concentrated in the phase of metastatic disease
Summary
Androgens are steroid hormones governing the development of male reproductive tract organs and secondary male sex characteristics, as well as functioning in the regulation of muscle mass, fat deposition, and function of steroid hormone-sensitive neurons (Werner and Holterhus, 2014). The most prevalent genetic rearrangement in prostate cancer involves the fusion of the androgen-regulated gene TMPRSS2 with the ETS transcription factor ERG, which is estimated to occur in ∼50% of prostate cancer cases (Tomlins et al, 2005; Kumar-Sinha et al, 2008) being by far the single most common genetic fusion gene in solid tumors (PCAWG Transcriptome Core Group et al, 2020).
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