| Summary: | 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.
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