Nts, such as LY3039478 site splicing enhancers and silencers, causing aberrant alternative splicing. Additionally, genomic mutations can generate a cryptic splice site along with disruption of a canonical one. These mutations, which lead to production of aberrant splice 
isoforms, could have a profound impact on tumor development and progression. The Kruppel-like factor 6 gene encodes a Zn-finger transcription factor and functions as a tumor suppressor. Interestingly, a germline single nucleotide polymorphism in intron 1 of the KLF6 gene is associated with PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19850275 high risk of prostate MedChemExpress TMS cancer174. This point mutation generates a binding site for the SR protein SRSF5, resulting in preferential usage of cryptic splicing sites in KLF6 exon 2174. Consequently, the produced splice variants, KLF-SVs, antagonize wild-type KLF6, promoting prostate cancer progression174, 175. Moreover, ectopic expression of the KLF6-SV1 splice isoform promotes an EMT phenotype and breast cancer metastasis, and its expression correlates with poor survival of breast cancer patients176. The germline mutation of BRCA1 can also cause aberrant alternative splicing in cancer. The tumor suppressor gene BRCA1 is involved in DNA damage repair by forming a BRCA1associated genome surveillance complex through protein interactions177. Individuals with BRCA1 mutations show high risk of ovarian and breast cancers. An inherited G-to-T nonsense point mutation in BRCA1 exon 18 may disrupt an SRSF1binding site necessary for the inclusion of exon 18178180. At the same time, this mutation creates a binding site for splicing inhibitors hnRNPA1/A2 and DAZAP1, resulting in exon skipping181. Exon 18 exclusion eliminates the first BRCT domain, Wiley Interdiscip Rev RNA. Author manuscript; available in PMC 2015 May 10. Liu and Cheng Page 11 through which BRCA1 interacts with various DNA damage proteins182, 183, thus generating a non-functional BRCA1 mutant protein. These observations illustrate that cis-element mutations can cause aberrant alternative splicing that affects the function of coding genes. Regulation of alternative splicing through trans-acting factors In addition to cis-acting element mutations, trans-acting regulators, i.e. splicing factors, can also be aberrantly regulated at multiple levels, including genomic mutation, transcriptional regulation, post-transcriptional regulation, and post-translational regulation. Mutations in splicing factors–Exome sequencing has demonstrated great power in uncovering somatic mutations that are associated with diseases. Recent identifications of mutations in the SF3B1 and U2AF35 genes in hematopoietic malignancies and other solid tumors suggested a novel means of RNA splicing deregulation that could be a driver for the development of various types of tumors184189. Especially in myelodysplastic syndromes and myelodysplasia, as many as 4585% of patients have mutations in the RNA splicing machinery184. These mutations occur in a mutually exclusive manner, and the mutated genes are involved in the 3′-splice site recognition during splicing. Importantly, introducing the U2AF35 mutant found in patients into cancer cells resulted in enrichment in unspliced introns and increased expression of members of the NMD pathway184. It was suggested that these spliceosomal pathway mutations compete with normal splicing machinery, leading to pathogenesis. It will be interesting to investigate the functional connections between these mutations and disease phenotypes. Transcriptional.Nts, such as splicing enhancers and silencers, causing aberrant alternative splicing. Additionally, genomic mutations can generate a cryptic splice site along with disruption of a canonical one. These mutations, which lead to production of aberrant splice isoforms, could have a profound impact on tumor development and progression. The Kruppel-like factor 6 gene encodes a Zn-finger transcription factor and functions as a tumor suppressor. Interestingly, a germline single nucleotide polymorphism in intron 1 of the KLF6 gene is associated with PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19850275 high risk of prostate cancer174. This point mutation generates a binding site for the SR protein SRSF5, resulting in preferential usage of cryptic splicing sites in KLF6 exon 2174. Consequently, the produced splice variants, KLF-SVs, antagonize wild-type KLF6, promoting prostate cancer progression174, 175. Moreover, ectopic expression of the KLF6-SV1 splice isoform promotes an EMT phenotype and breast cancer metastasis, and its expression correlates with poor survival of breast cancer patients176. The germline mutation of BRCA1 can also cause aberrant alternative splicing in cancer. The tumor suppressor gene BRCA1 is involved in DNA damage repair by forming a BRCA1associated genome surveillance complex through protein interactions177. Individuals with BRCA1 mutations show high risk of ovarian and breast cancers. An inherited G-to-T nonsense point mutation in BRCA1 exon 18 may disrupt an SRSF1binding site necessary for the inclusion of exon 18178180. At the same time, this mutation creates a binding site for splicing inhibitors hnRNPA1/A2 and DAZAP1, resulting 
in exon skipping181. Exon 18 exclusion eliminates the first BRCT domain, Wiley Interdiscip Rev RNA. Author manuscript; available in PMC 2015 May 10. Liu and Cheng Page 11 through which BRCA1 interacts with various DNA damage proteins182, 183, thus generating a non-functional BRCA1 mutant protein. These observations illustrate that cis-element mutations can cause aberrant alternative splicing that affects the function of coding genes. Regulation of alternative splicing through trans-acting factors In addition to cis-acting element mutations, trans-acting regulators, i.e. splicing factors, can also be aberrantly regulated at multiple levels, including genomic mutation, transcriptional regulation, post-transcriptional regulation, and post-translational regulation. Mutations in splicing factors–Exome sequencing has demonstrated great power in uncovering somatic mutations that are associated with diseases. Recent identifications of mutations in the SF3B1 and U2AF35 genes in hematopoietic malignancies and other solid tumors suggested a novel means of RNA splicing deregulation that could be a driver for the development of various types of tumors184189. Especially in myelodysplastic syndromes and myelodysplasia, as many as 4585% of patients have mutations in the RNA splicing machinery184. These mutations occur in a mutually exclusive manner, and the mutated genes are involved in the 3′-splice site recognition during splicing. Importantly, introducing the U2AF35 mutant found in patients into cancer cells resulted in enrichment in unspliced introns and increased expression of members of the NMD pathway184. It was suggested that these spliceosomal pathway mutations compete with normal splicing machinery, leading to pathogenesis. It will be interesting to investigate the functional connections between these mutations and disease phenotypes. Transcriptional.