title: RNA splicing and splicing regulator changes in prostate cancer pathology.
abstract: 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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, England, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Munkley
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, England, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Livermore
authors.affiliation: Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors.forename: Prabhakar
authors.initials: P
authors.lastname: Rajan
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, England, UK. David.Elliott@ncl.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Elliott
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D012326:RNA Splicing; D012333:RNA, Messenger; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489559:KHDRBS1 protein, human; C513253:Khdrbs1 protein, mouse; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; C000595377:SRRM4 protein, human; C097083:TRA2B protein, human; C100345:Tra2b protein, mouse; D000068103:Serine-Arginine Splicing Factors; C087728:SRPK1 protein, human; C490215:Srpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Abiraterone; Androgen Deprivation Therapy; Androgen Receptor; Prostate Cancer; Prostate Cancer Cell