How Driver Oncogenes Shape and Are Shaped by Alternative Splicing Mechanisms in Tumors

Abstract

The development of RNA sequencing methods has allowed us to study and better understand the landscape of aberrant pre-mRNA splicing in tumors. Altered splicing patterns are observed in many different tumors and affect all hallmarks of cancer: growth signal independence, avoidance of apoptosis, unlimited proliferation, invasiveness, angiogenesis, and metabolism. In this review, we focus on the interplay between driver oncogenes and alternative splicing in cancer. On one hand, oncogenic proteins-mutant p53, CMYC, KRAS, or PI3K-modify the alternative splicing landscape by regulating expression, phosphorylation, and interaction of splicing factors with spliceosome components. Some splicing factors-SRSF1 and hnRNPA1-are also driver oncogenes. At the same time, aberrant splicing activates key oncogenes and oncogenic pathways: p53 oncogenic isoforms, the RAS-RAF-MAPK pathway, the PI3K-mTOR pathway, the EGF and FGF receptor families, and SRSF1 splicing factor. The ultimate goal of cancer research is a better diagnosis and treatment of cancer patients. In the final part of this review, we discuss present therapeutic opportunities and possible directions of further studies aiming to design therapies targeting alternative splicing mechanisms in the context of driver oncogenes.

Keywords: CMYC; KRAS; alternative splicing; mutant p53; splicing factors.

Figure 1

Effects of CMYC on splicing (blue arrows) and the influence of altered splicing on CMYC (green arrows). Red arrows: increased expression; AS: alternative splicing; SF: splicing factor.

Figure 2

Effects of KRAS on splicing (blue arrows) and influence of altered splicing on KRAS (green arrows). AS: alternative splicing; red arrows: increased expression or pathway activity.

Figure 3

The human TP53 gene and p53 isoforms. (Upper panel): schematic representation of TP53 gene. Exons are numbered from 1 to 11. Alternative splicing of introns i2 and i9 provides alternative p53 isoforms. P1 and P2: alternative promoters. ATG1 and ATG40: alternative transcription start sites. (Lower panel): representation of p53 domains. TAD: transactivation domain; PRD: proline rich domain; DBD: DNA binding domain; NLS: nuclear localization signal; OD: oligomerization domain; NRD: negative regulation domain. Isoforms β and γ lack C-terminal domains, including OD, replaced by DQTSFQKENC and MLLDLRWCYFLINSS, respectively. Isoforms Δ40p53, Δ133p53, and Δ160p53 have a deletion from N-terminus.