RNA Splicing and Cancer

Tumor cells alter the expression of RBP splicing factors to promote splicing associated with a tumorigenic state. The splicing machinery is frequently mutated in cancers and exerts differential effects on splicing but converges on downstream signaling pathways. Neoepitopes can arise from aberrant splicing in cancer cells and signify a new avenue as immunotherapeutic targets. A repertoire of therapeutic approaches has been developed to target splicing alterations across several cancers. RNA splicing is an essential process that governs many aspects of cellular proliferation, survival, and differentiation. Considering the importance of RNA splicing in gene regulation, alterations in this pathway have been implicated in many human cancers. Large-scale genomic studies have uncovered a spectrum of splicing machinery mutations that contribute to tumorigenesis. Moreover, cancer cells are capable of hijacking the expression of RNA-binding proteins (RBPs), leading to dysfunctional gene splicing and tumor-specific dependencies. Advances in next-generation RNA sequencing have revealed tumor-specific isoforms associated with these alterations, including the presence of neoantigens, which serve as potential immunotherapeutic targets. In this review, we discuss the various mechanisms by which cancer cells exploit RNA splicing to promote tumor growth and the current therapeutic landscape for splicing-based therapies. RNA splicing is an essential process that governs many aspects of cellular proliferation, survival, and differentiation. Considering the importance of RNA splicing in gene regulation, alterations in this pathway have been implicated in many human cancers. Large-scale genomic studies have uncovered a spectrum of splicing machinery mutations that contribute to tumorigenesis. Moreover, cancer cells are capable of hijacking the expression of RNA-binding proteins (RBPs), leading to dysfunctional gene splicing and tumor-specific dependencies. Advances in next-generation RNA sequencing have revealed tumor-specific isoforms associated with these alterations, including the presence of neoantigens, which serve as potential immunotherapeutic targets. In this review, we discuss the various mechanisms by which cancer cells exploit RNA splicing to promote tumor growth and the current therapeutic landscape for splicing-based therapies. located at the 3′ end of the intron and essential for correct RNA splicing. gene isoforms that arise specifically in tumorigenic states compared with normal tissues. receptor proteins that have been engineered into T cells to target a specific protein. age-related expansion of blood cells that arise from clonal hematopoietic cells. sequences that are typically not recognized by the spliceosome, however, mutations at canonical splice sites can lead to the activation of cryptic splice sites being used. monoclonal antibodies that target immune checkpoints. a type of alternative splicing in which an intron that is retained contains stop codons or a shift in the reading frame, consequently leading to mRNA degradation. differential usage of gene isoforms in response to a signal. surveillance pathway for degrading mRNA transcripts that contain premature stop codons. an exon that contains premature stop codons during alternative splicing and triggers the transcript to undergo nonsense mediated decay. a nucleic acid structure that is composed of a DNA: RNA hybrid and a nontemplate single-stranded DNA. Dissolution of R-loops is mediated by RNase H and unwarranted formation of R-loops induces genomic instability. substitution of a single nucleotide at a specific DNA sequence that can be found on protein-coding genes, noncoding sequences, and intergenic regions. co-occurrence of two or more genetic interactions that lead to cellular death. rare group of introns that do not contain the typical consensus sequences (splice site and branch point) and therefore utilize a minor spliceosome complex for RNA splicing.