The Cancer Spliceome: Reprograming of Alternative Splicing in Cancer

Abstract

Alternative splicing allows for the expression of multiple RNA and protein isoforms from one gene, making it a major contributor to transcriptome and proteome diversification in eukaryotes. Advances in next generation sequencing technologies and genome-wide analyses have recently underscored the fact that the vast majority of multi-exon genes under normal physiology engage in alternative splicing in tissue-specific and developmental-specific manner. On the other hand, cancer cells exhibit remarkable transcriptome alterations partly by adopting cancer-specific splicing isoforms. These isoforms and their encoded proteins are not insignificant byproducts of the abnormal physiology of cancer cells, but either drivers of cancer progression or small but significant contributors to specific cancer hallmarks. Thus, it is paramount that the pathways that regulate alternative splicing in cancer, including the splicing factors that bind to pre-mRNAs and modulate spliceosome recruitment. In this review, we present a few distinct cases of alternative splicing in cancer, with an emphasis on their regulation as well as their contribution to cancer cell phenotype. Several categories of splicing aberrations are highlighted, including alterations in cancer-related genes that directly affect their pre-mRNA splicing, mutations in genes encoding splicing factors or core spliceosomal subunits, and the seemingly mutation-free disruptions in the balance of the expression of RNA-binding proteins, including components of both the major (U2-dependent) and minor (U12-dependent) spliceosomes. Given that the latter two classes cause global alterations in splicing that affect a wide range of genes, it remains a challenge to identify the ones that contribute to cancer progression. These challenges necessitate a systematic approach to decipher these aberrations and their impact on cancer. Ultimately, a sufficient understanding of splicing deregulation in cancer is predicted to pave the way for novel and innovative RNA-based therapies.

Role of alternative splicing signatures in the prognosis of glioblastoma

“…48 The splicing variants of TP53, FAS, CASP9, and BCL2L1 have been associated with cancer cell apoptosis and survival. 18, 49 Calabretta's study showed that modulating the pyruvate kinase gene (PKM) splicing could promote gemcitabine resistance in pancreatic cancer cells. 50 Recently, studies have focused on investigating the potential therapeutic value of AS in cancers.…”

Conventional and unconventional interactions of the transcription factor FOXL2 uncovered by a proteome‐wide analysis

“…Patterns of mRNA alternative splicing and maturation are often altered in cancer, and alternative splicing deregulations can be considered as oncogenic, in a similar manner as driver mutations in oncogenes or tumor suppressors. 77,78 Given the interaction between FOXL2 and the mRNA processing machinery, in particular the spliceosome, we hypothesize that the implication of mutated FOXL2 in tumorigenesis is not only due to transcription dysregulation but also to altered mRNA processing.…”

Characterization of unique PMEPA1 gene splice variants (isoforms d and e) from RNA Seq profiling provides novel insights into prognostic evaluation of prostate cancer

“…These features suggested that the long luminal region in PMEPA1-e may be due to the retention of intron. Intron retention was one of the alternative splicing mechanisms requiring both suboptimal 5′ and 3′ splice sites, which was often overlooked or interpreted as splicing mistake where intron was not spliced out [23,27,28]. Enhanced levels of retained introns were usually noted in cancer cells, leading to higher diversity in cancer transcriptomes [22].…”

“…The alternative splicing variant mechanism had also been shown to be important for diversifying functions of tumor-associated genes. The RNA splicing mechanism across the tumors allowed the expressions of multiple RNA and protein isoforms from one gene, serving as a major contributor to diversities of transcriptomes and proteomes [22,23]. The previous studies had implied splicing variants mechanism accounted for the formation of PMEPA1 gene isoforms and its multi-functional features in tumorigenesis.…”