Aberrant RNA splicing is thought to play a key role in
tumorigenesis. The assessment of its specific contributions is limited by the complexity of information derived from genome-wide array-based approaches. We describe how performing
splicing factor-specific comparisons using both
tumor and cell line data sets may more readily identify physiologically relevant
tumor-specific splicing events. Affymetrix exon array data derived from
glioblastoma (GBM)
tumor samples with defined
polypyrimidine tract-binding protein 1 (PTBP1) levels were compared with data from U251 GBM cells with and without PTBP1 knockdown. This comparison yielded overlapping gene sets that comprised only a minor fraction of each data set. The identification of a novel GBM-specific splicing event involving the USP5 gene led us to further examine its role in
tumorigenesis. In GBM, USP5 generates a shorter
isoform 2 through recognition of a
5' splice site within exon 15. Production of the USP5
isoform 2 was strongly correlated with PTBP1 expression in GBM
tumor samples and cell lines. Splicing regulation was consistent with the presence of an intronic PTBP1 binding site and could be modulated through antisense targeting of the
isoform 2 splice site to force expression of
isoform 1 in GBM cells. The forced expression of USP5
isoform 1 in two GBM cell lines inhibited cell growth and migration, implying an important role for USP5 splicing in gliomagenesis. These results support a role for aberrant RNA splicing in
tumorigenesis and suggest that changes in relatively few genes may be sufficient to drive the process.