WNT REGULATED DIFFERENTIAL GENE ISOFORM EXPRESSION IN CANCER

Abstract

Differential gene isoform expression is a ubiquitous mechanism that enhances proteome diversity and regulates cell homeostasis. Splicing events are highly dynamic and can respond to changes induced by cell signaling pathways. Wnt signaling is known to modify several splicing events by altering the expression of specific splicing factors. However, a global assessment of how extensively Wnt signaling regulates splicing in cancer is lacking. RNA-Seq datasets from two independent in vivo Wnt-addicted tumor models treated with the Wnt signaling inhibitor ETC-159, were used to examine Wnt regulated differential splicing events. Over 1,000 genes were found to be differentially spliced in a Wnt-dependent manner, coupled to extensive Wnt-regulated changes in the expression of splicing regulators. Many of these Wnt-regulated splicing events were conserved in multiple human cancers and many were linked to cancer-associated splicing quantitative trait loci. These findings provide a resource of Wnt regulated splicing events and splicing effector proteins.