Oncogenic alternative splicing switches: role in cancer progression and prospects for therapy

Abstract

Alterations in the abundance or activities of alternative splicing regulators generate alternatively spliced variants that contribute to multiple aspects of tumor establishment, progression and resistance to therapeutic treatments. Notably, many cancer-associated genes are regulated through alternative splicing suggesting a significant role of this post-transcriptional regulatory mechanism in the production of oncogenes and tumor suppressors. Thus, the study of alternative splicing in cancer might provide a better understanding of the malignant transformation and identify novel pathways that are uniquely relevant to tumorigenesis. Understanding the molecular underpinnings of cancer-associated alternative splicing isoforms will not only help to explain many fundamental hallmarks of cancer, but will also offer unprecedented opportunities to improve the efficacy of anti-cancer treatments.

Figure 1

SRFs (splicing regulatory factors) at the cross-road between oncogenic signaling pathways and targets for anticancer treatments. During tumorigenesis, cancer cells are exposed to stressing conditions such as hypoxia and acidosis. In this altered tumor microenvironment, growth factors and cytokines, provided by either cancer or non-tumoral cells, activate signaling cascades affecting both the activity and/or the expression levels of splicing regulatory factors (SRFs). In the cytoplasm, SRSFs can enhance the translation of oncogenic variants involved in key aspects of cancer cell biology. In the nucleus, SRFs are mainly involved in the regulation of alternative splicing of pre-mRNAs relevant to cancer progression mechanisms, namely, pro-liferation, angiogenesis, survival, invasion, and metastasis. Alternative splicing variants of cancer-related genes represent powerful targets for new therapeutic approaches. (a) Alternative splicing can generate unique epitopes in cell surface proteins that can be targeted by monoclonal antibodies (mAbs), able to lead to down-regulation or neutralization of the specific isoforms. Moreover, mAbs can be also used to selectively deliver bioactive molecules to cancer cells without affecting normal tissues. (b) Small molecules, by interfering with the spliceosome assembly or with the phosphorylation status of SRFs (i.e., SR proteins), can in turn affect the balance of alternative splicing products, preventing the generation of cancer-associated variants. (c) Standard ASOs (antisense oligonucleotides) block the interaction between the splicing machinery and the cognate splicing sequences (splice sites, enhancer or silencer elements), whereas TOES (targeted oligonucleotide enhancers of splicing) oligonucleotides contain a “tail” of ESE sequences to recruit SRFs on a specific alternative exon. By inhibiting or activating specific splicing events, TOES can be used to shift the ratio between biologically functional splice variants toward the production of non-pathological isoforms.