Identification of RNA binding proteins associated with differential splicing in neuroendocrine prostate cancer

• Main Author: Yeung, Jake
• Language: English
• Published: University of British Columbia 2014
• Online Access: http://hdl.handle.net/2429/46688

Alternative splicing is a tightly regulated process that can be disrupted in cancer. Established cancer genes express splice isoforms with distinct properties and their differential expression is associated with tumour progression. Although prostate adenocarcinoma (PCa) is effectively managed at early stage by therapies targeting the androgen receptor signaling axis, up to 30% of late stage prostate cancers progress to a treatment-resistant form of the disease called neuroendocrine prostate cancer (NEPC), for which there are few therapeutic options. It is histologically distinct from PCa, expresses a neuronal gene signature and is associated with poor survival (<1 year). We hypothesize that alternative splicing has an important role in driving transformation of PCa tumours towards the NEPC phenotype and we seek to identify regulators of aberrant alternative splicing. We integrated a number of bioinformatics tools to investigate alternative splicing in NEPC. Analyzing RNA-Seq data from a patient-derived xenograft model of neuroendocrine transdifferentiation, we compared splicing profiles between NEPC and PCa and identified a set of differentially spliced cassette exons. We found these cassette exons to code for protein segments containing DNA-binding domains, protein-binding regions and posttranslational modification sites. We discovered evolutionarily conserved motifs around intronic regions of the cassette exons and implicated them with RNA recognition motifs of tissue-specific RNA binding proteins. We corroborated our findings by analyzing RNA-Seq data from a patient-tumour cohort and found recurrent RNA binding proteins associated with cassette exon inclusion. Our integrated analysis suggests that splicing changes between PCa and NEPC are mediated by tissue-specific RNA binding proteins, which may be of therapeutic or diagnostic value.