Alternative splicing: Role in cancer development and progression

Alternative splicing of precursor messenger RNAs (premRNAs) is a fundamental step in the regulation of gene expression. This processing step of the nascent messenger amplifies the coding potential of eukaryotic genomes by allowing the production of multiple protein isoforms with distinct structural and functional properties. The advent of high-throughput sequencing techniques has recently revealed that alternative splicing of exons and introns represents a major source of proteomic diversity in complex organisms characterized by a limited number of protein-coding genes. Nevertheless, the evolutionary advantage provided by alternative splicing can also turn into a source of deleterious problems for the organism. Indeed, the extreme flexibility of its regulation, which relies on the combinatorial action of multiple non stringent factors, is subject to errors and the aberrant splicing of key genes can result in the onset of many human genetic and sporadic diseases. In this regard, mounting evidence illustrates how changes in alternative splicing patterns of specific genes is an important tool used by cancer cells to produce protein isoforms involved in all areas of cancer cell biology, including numerous aspects of tumor establishment, progression, and resistance to therapeutic treatments. Importantly, cancer-specific splice variants have the potential to become suitable therapeutic targets for human cancer, as novel tools to correct splicing defects are being developed and, in some cases, have entered clinical trials for other human diseases, such as spinal muscular atrophy. Nevertheless, these findings are likely to represent just the tip of the iceberg and important questions regarding the role of alternative splicing in cancer still remain to be addressed. The main focus of this special issue is to emphasize key mechanisms involved in oncogenic splicing changes, their connection with other steps of gene expression, and the therapeutic potential of cancer-associated alternative splicing isoforms. More specifically, M. Ladomery discusses alternative splicing in the context of the so-called hallmarks of cancer, originally proposed by Hanahan and Weinberg in 2000. The list of hallmarks was originally six; recently it was augmented to ten. M. Ladomery proposes that a comprehensive dysregulation of alternative splicing could, in itself, be considered yet another hallmark of cancer. The idea is that the aberrant expression and activity of key oncogenic splicing factors and/or their regulatory kinases could lead to a systematic change in gene expression by favouring the concurrent production of several oncogenic splice variants of genes involved in critical biological aspects of tumour cells. S. C. Lenzken et al. review our current knowledge of the role of alternative splicing in the multiple and various aspects of the DNA damage response (DDR) and the control of genome stability. This review illustrates several mechanisms through which pre-mRNA splicing and genomic stability can influence each other and contribute to tumorigenesis. M. Romano and colleagues draw attention to the function that pseudoexons and pseudointrons can play directly in cancer pathology. These sequences can be found in genes that have well-established roles in cancer, including BRCA1, 2 International Journal of Cell Biology BRCA2, NF-1, and ATM. They describe the mechanisms through which pseudoexons and pseudointrons can be activated or repressed. In addition, they discuss their potential use as tumour biomarkers to provide a more detailed staging and grading of cancer. C. Naro and C. Sette discuss the key role that reversible phosphorylation plays in the regulation of alternative splicing. Both splice factors and core components of the spliceosome are affected by phosphorylation. The review focuses on the role of protein kinases and phosphatases whose activity has specifically been linked to