The spliceosome machinery is composed of multimeric protein complexes that 
generate a diverse repertoire of mRNA through coordinated splicing of 
heteronuclear RNAs. While somatic mutations in spliceosome components have been 
discovered in several cancer types, the molecular bases and consequences of 
spliceosome aberrations in cancer are poorly understood. Here we report for the 
first time that PRPF6, a member of the tri-snRNP (small ribonucleoprotein) 
spliceosome complex, drives cancer proliferation by preferential splicing of 
genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP 
complex proteins, but not other snRNP spliceosome complexes, selectively 
abrogated growth in cancer cells with high tri-snRNP levels. High-resolution 
transcriptome analyses revealed that reduced PRPF6 alters the constitutive and 
alternative splicing of a discrete number of genes, including an oncogenic 
isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 
in cancer via splicing of distinct growth-related gene products.