The role of mRNA splicing in prostate cancer

Abstract

Alternative splicing (AS) is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer (PCa) AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa: androgen receptor (AR) and phosphoinositide 3-kinase (PI3K). These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.

Figure 1

Functional alternative splicing in prostate cancer. Splice isoforms differentially regulated in prostate cancer are indicated with light red (up-regulated) and light green (down-regulated).

Figure 2

Splicing regulation of the androgen receptor (AR) and phosphoinositide 3-kinase (PI3K) signaling pathways. Members of the pathway whose transcripts are alternatively spliced in cancer are indicated with green decagons. Splice factors Sam68, SRSF1, and SRs as well as their regulators (SRPKs) that are altered in cancer transcriptionally or post-transcriptionally are marked with green ovals. Dark green indicates that altered function of a splice isoform or a splice factor has been observed in prostate cancer whereas light green–in other cancers. SRs: splice factors of the serine/arginine-rich protein family; SRPKs: SR protein kinases; p: phosphorylation; AS: alternative splicing. The signaling pathways of AR and PI3K have been adapted from Barlow and Shen. ^*Pathway components for which new blocking agents are under investigation for advanced prostate cancer.

Figure 3

REST-mediated transcriptome reprogramming in neuroendocrine transdifferentiation. The REST transcriptional complex represses transcription of neuronal genes through binding to the regulatory RE1 sites located within promoter or enhancer regions of genes. This complex undergoes transcriptional and post-transcriptional changes during neuroendocrine transdifferentiation. REST transcripts are transcriptionally attenuated and alternatively spliced and the REST cofactor BHC80 is alternative spliced. The resulting REST and BHC80 isoforms lack important functional domains necessary for the repression (REST4 isoform and the NEPC-specific BHC80 isoform). Loss of REST-mediated repression leads to the emergence of the neuronal transcriptional program, including NEPC-specific splicing.