REVIEW Misregulation of Pre-mRNA Alternative Splicing in Cancer

ABSTRACT Alternative splicing of mRNA precursors enables one gene to produce multiple protein isoforms with differing functions. Under normal conditions, this mechanism is tightly regulated in order for the human genome to generate proteomic diversity suffi cient for the functional requirements of complex tissues. When deregulated, however, cancer cells take advantage of this mechanism to produce aberrant proteins with added, deleted, or altered functional domains that contribute to tumorigenesis. Here, we discuss aspects of alternative splicing misregulation in cancer, focusing on splicing events affected by deregulation of regulatory splicing factors and also recent stud-ies identifying mutated components of the splicing machinery. Signifi cance: An increasing body of evidence indicates that aberrant splicing of mRNA precursors leads to production of aberrant proteins that contribute to tumorigenesis. Recent studies show that altera-tions in cellular concentrations of regulatory splicing factors and mutations in components of the core splicing machinery provide major mechanisms of misregulation of mRNA splicing in cancer. A better understanding of this misregulation will potentially reveal a group of novel drug targets for therapeutic intervention. Cancer Discov; 3(11); 1228–37. ©2013 AACR