RNA splicing and splicing regulator changes in prostate cancer pathology.

["Munkley J", "Livermore K", "Rajan P", "Elliott D"]

Human genetics 2017

Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor gene TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2-ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2β increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.

4 Figures Extracted

Fig. 1 PMC

Different kinds of splicing pattern and their effect on prostate cancer cell biology. The most common form of alternative splicing in human cells is s...

Fig. 2 PMC

Prostate tissue visualised using tissue biopsies. a , b . Histological sections made from benign prostatic hyperplasia (BPH, with normal glandular s...

Fig. 3 PMC

Transcriptional control by a the full-length androgen receptor and b constitutively active AR isoforms made by splice variants. In ( a ), testoste...

Fig. 4 PMC

Exon–intron organisation of the AR gene and frequent pathogenic AR mRNA splice isoforms. a The AR protein is encoded by the 8-exon AR gene on ...