Splicing-factor alterations in cancers

Abstract

Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

FIGURE 1.

Splicing-factor alterations in human tumors. Human tumors exhibit somatic mutations in splicing regulators, or changes in splicing-factor levels in response to cell signaling or transcriptional regulation. These alterations in splicing factors promote differential splicing patterns in tumors compared to normal tissues. Alterations in alternative splicing events lead to the production of pro-tumorigenic isoforms that have been linked to various steps of tumorigenesis, including proliferation, apoptosis, invasion, metabolism, angiogenesis, DNA damage, or even drug resistance and immune response.

FIGURE 2.

Recurrent splicing-factor mutations in human malignancies. Hotspot mutations in the genes coding for splicing factors U2AF1, SRSF2, and SF3B1 detected in myelodysplasia, as well as other tumor types, are indicated. In contrast, ZRSR2 mutations are distributed evenly across the gene (not shown). Domain abbreviations: (Zn) zinc finger domain, (UHM) U2AF homology motif domain, (RS) arginine/serine-rich domain, (RRM) RNA-recognition motif, (HD) heat domain.

FIGURE 3.

Model for SRSF1's roles in transformation in breast cancer. Increased expression of SRFS1 in human tumors results from several distinct types of alterations, such as amplification of the Chr. 17q23 amplicon, transcriptional regulation of SRFS1 downstream from MYC, or splicing regulation of SRSF1 pre-mRNA by Sam68. Up-regulation of SRSF1 promotes splicing changes in target genes involved in apoptosis, cell motility, proliferation, and other cellular functions. SRSF1 activates splicing by binding to an exonic motif recognized by its RRM1. SRSF1 overexpression promotes expression of anti-apoptotic isoforms unable to interact with pro-apoptotic factors, or that inhibit the action of pro-apoptotic factors, such as MYC or members of the Bcl-2 family. In parallel, SRSF1 overexpression promotes expression of isoforms that stimulate translation and cell proliferation by increasing phosphorylation of translation activators, such as S6 or eIF4E, or by inhibiting translational repressors, such as 4EBP1. In addition, MYC can cooperate with SRSF1 in transformation, and has a synergistic effect in the activation of the eIF4E pathway. By increasing proliferation and decreasing apoptosis, SRSF1 promotes cellular transformation in mammary epithelial cells.

FIGURE 4.

Domain structure of splicing factors altered in solid tumors. The chromosomal locus of each splicing-factor-encoding human gene is shown on the left. For each RNA-binding protein (RBP) representative of the indicated families, the annotated protein domains or regions are shown in the diagrams (see legend for details), along with the size (in amino acids) of the human protein.