CoChat
Sign Up
Cited by 579RNA Research and SplicingCancer-related molecular mechanisms researchRNA regulation and disease

RNA splicing dysregulation and the hallmarks of cancer

Open access
Bradley, Robert K., Anczuków, Olga·2023·Nature Reviews Cancer
DOI 10.1038/s41568-022-00541-7PMC PMC10132032
Open this paper in CoChat — free accountOpen PDF

Abstract

Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations and altered expression of trans-acting factors governing splicing catalysis and regulation. Cancer-associated splicing dysregulation can promote tumorigenesis via diverse mechanisms, contributing to increased cell proliferation, decreased apoptosis, enhanced migration and metastatic potential, resistance to chemotherapy and evasion of immune surveillance. Recent studies have identified specific cancer-associated isoforms that play critical roles in cancer cell transformation and growth and demonstrated the therapeutic benefits of correcting or otherwise antagonizing such cancer-associated mRNA isoforms. Clinical-grade small molecules that modulate or inhibit RNA splicing have similarly been developed as promising anticancer therapeutics. Here, we review splicing alterations characteristic of cancer cell transcriptomes, dysregulated splicing's contributions to tumour initiation and progression, and existing and emerging approaches for targeting splicing for cancer therapy. Finally, we discuss the outstanding questions and challenges that must be addressed to translate these findings into the clinic.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41568-022-00541-7

Cites

16 of 16 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Dysregulation of RNA processing and miRNA-mediated gene silencing is associated with an increasing number of human diseases, including cancer.

    “and their dysregulation is associated with an increasing number of human diseases, including cancer (Manning and Cooper 2017; Bradley and Anczuków 2023; Rogalska et al. 2023).”

    From ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation (2025) · cites this paper as Bradley and Anczuków 2023

    The Introduction and Abstract link dysregulated RNA splicing to cancer, describing splicing abnormalities across tumors. They do not establish the claim about miRNA-mediated gene silencing or an increasing number of human diseases; the paper focuses on splicing and cancer. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 257

  1. [1]Black DL Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72, 291– 336, doi: 10.1146/annurev.biochem.72.121801.161720 (2003). 12626338 · DOI · Paper page
  2. [2]Reixachs-Sole M & Eyras E Uncovering the impacts of alternative splicing on the proteome with current omics techniques. Wiley Interdiscip Rev RNA 13, e1707, doi: 10.1002/wrna.1707 (2022). 34979593 PMC9542554 · DOI
  3. [3]Blencowe BJ Alternative splicing: new insights from global analyses. Cell 126, 37– 47, doi: 10.1016/j.cell.2006.06.023 (2006). 16839875 · DOI
  4. [4]Wang ET Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470– 476, doi: 10.1038/nature07509 (2008). 18978772 PMC2593745 Landmark study using RNA-seq to quantify isoform expression across tissues. · DOI · Paper page
  5. [5]Kahles A Comprehensive Analysis of Alternative Splicing Across Tumors from 8,705 Patients. Cancer Cell 34, 211– 224.e216, doi: 10.1016/j.ccell.2018.07.001 (2018). 30078747 PMC9844097 Landmark study identifying splicing alterations across tumor types. · DOI
  6. [6]Urbanski LM, Leclair N & Anczukow O Alternative-splicing defects in cancer: Splicing regulators and their downstream targets, guiding the way to novel cancer therapeutics. Wiley Interdiscip Rev RNA 9, 1476, doi: 10.1002/wrna.1476 (2018). PMC6002934 29693319 · DOI
  7. [7]Dvinge H, Kim E, Abdel-Wahab O & Bradley RK RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 16, 413– 430, doi: 10.1038/nrc.2016.51 (2016). 27282250 PMC5094465 · DOI
  8. [8]Stanley RF & Abdel-Wahab O Dysregulation and therapeutic targeting of RNA splicing in cancer. Nat Cancer 3, 536– 546, doi: 10.1038/s43018-022-00384-z (2022). 35624337 PMC9551392 · DOI
  9. [9]Bonnal SC, López-Oreja I & Valcárcel J Roles and mechanisms of alternative splicing in cancer — implications for care. Nature Reviews Clinical Oncology 17, 457– 474, doi: 10.1038/s41571-020-0350-x (2020). 32303702 · DOI
  10. [11]Hanahan D & Weinberg RA The hallmarks of cancer. Cell 100, 57– 70, doi: 10.1016/s0092-8674(00)81683-9 (2000). 10647931 · DOI · Paper page
  11. [12]Wilkinson ME, Charenton C & Nagai K RNA Splicing by the Spliceosome. Annu Rev Biochem 89, 359– 388, doi: 10.1146/annurev-biochem-091719-064225 (2020). 31794245 · DOI
  12. [13]Akinyi MV & Frilander MJ At the Intersection of Major and Minor Spliceosomes: Crosstalk Mechanisms and Their Impact on Gene Expression. Frontiers in Genetics 12, 700744, doi: 10.3389/fgene.2021.700744 (2021). 34354740 PMC8329584 · DOI
  13. [14]Lee Y & Rio DC Mechanisms and Regulation of Alternative Pre-mRNA Splicing. Annu Rev Biochem 84, 291– 323, doi: 10.1146/annurev-biochem-060614-034316 (2015). 25784052 PMC4526142 · DOI · Paper page
  14. [15]Ellis JD Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol Cell 46, 884– 892, doi: 10.1016/j.molcel.2012.05.037 (2012). 22749401 · DOI · Paper page
  15. [16]Tung KF, Pan CY, Chen CH & Lin WC Top-ranked expressed gene transcripts of human protein-coding genes investigated with GTEx dataset. Sci Rep 10, 16245, doi: 10.1038/s41598-020-73081-5 (2020). 33004865 PMC7530651 · DOI
  16. [17]Howard JM & Sanford JR The RNAissance family: SR proteins as multifaceted regulators of gene expression. Wiley Interdiscip Rev RNA 6, 93– 110, doi: 10.1002/wrna.1260 (2015). 25155147 PMC4268343 · DOI
  17. [18]Geuens T, Bouhy D & Timmerman V The hnRNP family: insights into their role in health and disease. Hum Genet 135, 851– 867, doi: 10.1007/s00439-016-1683-5 (2016). 27215579 PMC4947485 · DOI
  18. [19]Papaemmanuil E Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med 365, 1384– 1395, doi: 10.1056/NEJMoa1103283 (2011). 21995386 PMC3322589 · DOI · Paper page
  19. [21]Harbour JW Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat Genet 45, 133– 135, doi: 10.1038/ng.2523 (2013). 23313955 PMC3789378 · DOI
  20. [22]Martin M Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet 45, 933– 936, doi: 10.1038/ng.2674 (2013). 23793026 PMC4307600 Harbour et al. and Martin et al. identified recurrent mutations in SF3B1 in uveal melanoma. · DOI
  21. [24]Lee SC Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations. Cancer Cell 34, 225– 241 e228, doi: 10.1016/j.ccell.2018.07.003 (2018). 30107174 PMC6373472 · DOI · Paper page
  22. [25]Taylor J Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms. Blood 136, 1477– 1486, doi: 10.1182/blood.2020006868 (2020). 32640014 PMC7515689 · DOI
  23. [26]Wang L SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 365, 2497– 2506, doi: 10.1056/NEJMoa1109016 (2011). 22150006 PMC3685413 Identified recurrent mutations in SF3B1 in CLL. · DOI
  24. [27]Alsafadi S Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat Commun 7, 10615, doi: 10.1038/ncomms10615 (2016). 26842708 PMC4743009 · DOI
  25. [28]Darman RB Cancer-Associated SF3B1 Hotspot Mutations Induce Cryptic 3’ Splice Site Selection through Use of a Different Branch Point. Cell Rep 13, 1033– 1045, doi: 10.1016/j.celrep.2015.09.053 (2015). 26565915 Demonstrated that recurrent SF3B1 mutations alter branch point selection. · DOI
  26. [29]Dalton WB The K666N mutation in SF3B1 is associated with increased progression of MDS and distinct RNA splicing. Blood Adv 4, 1192– 1196, doi: 10.1182/bloodadvances.2019001127 (2020). 32211880 PMC7160262 · DOI
  27. [30]Inoue D Spliceosomal disruption of the non-canonical BAF complex in cancer. Nature 574, 432– 436, doi: 10.1038/s41586-019-1646-9 (2019). 31597964 PMC6858563 Showed that SF3B1 mutations disrupt chromatin remodeling to promote tumorigenesis. · DOI
  28. [31]Lieu YK SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes. Proc Natl Acad Sci U S A 119, 2111703119, doi: 10.1073/pnas.2111703119 (2022). PMC8740767 34930825 · DOI
  29. [32]Clough CA Coordinated missplicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome. Blood 139, 2038– 2049, doi: 10.1182/blood.2021012652 (2022). 34861039 PMC8972092 · DOI
  30. [33]Yoshimi A Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis. Nature 574, 273– 277, doi: 10.1038/s41586-019-1618-0 (2019). 31578525 PMC6858560 Demonstrated genetic and functional interactions between SRSF2 and IDH2 in leukemia. · DOI
  31. [34]Robertson AG Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell 32, 204– 220 e215, doi: 10.1016/j.ccell.2017.07.003 (2017). 28810145 PMC5619925 · DOI
  32. [37]Graubert TA Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet 44, 53– 57, doi: 10.1038/ng.1031 (2012). PMC3247063 22158538 · DOI
  33. [38]Brooks AN A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PLoS One 9, 87361, doi: 10.1371/journal.pone.0087361 (2014). PMC3909098 24498085 · DOI
  34. [39]Ilagan JO U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Research 25, 14– 26, doi: 10.1101/gr.181016.114 (2015). 25267526 PMC4317169 · DOI
  35. [40]Smith MA U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nat Cell Biol 21, 640– 650, doi: 10.1038/s41556-019-0314-5 (2019). 31011167 PMC6679973 · DOI
  36. [41]Biancon G Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies. Mol Cell 82, 1107– 1122 e1107, doi: 10.1016/j.molcel.2022.02.025 (2022). 35303483 PMC8988922 · DOI
  37. [42]Damm F Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 119, 3211– 3218, doi: 10.1182/blood-2011-12-400994 (2012). 22343920 · DOI
  38. [44]Madan V Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome. Nat Commun 6, 6042, doi: 10.1038/ncomms7042 (2015). 25586593 PMC4349895 · DOI
  39. [45]Inoue D Minor intron retention drives clonal hematopoietic disorders and diverse cancer predisposition. Nat Genet 53, 707– 718, doi: 10.1038/s41588-021-00828-9 (2021). 33846634 PMC8177065 Showed that disruption of minor intron splicing by ZRSR2 mutations promotes clonal advantage. · DOI
  40. [46]Wang X, Song X & Yan X Effect of RNA splicing machinery gene mutations on prognosis of patients with MDS: A meta-analysis. Medicine (Baltimore) 98, e15743, doi: 10.1097/MD.0000000000015743 (2019). 31124956 PMC6571257 · DOI
  41. [49]Fei DL Impaired hematopoiesis and leukemia development in mice with a conditional knock-in allele of a mutant splicing factor gene U2af1. Proc Natl Acad Sci U S A 115, 10437– E10446, doi: 10.1073/pnas.1812669115 (2018). PMC6217397 30322915 · DOI
  42. [50]Mian SA SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment. Nat Commun 6, 10004, doi: 10.1038/ncomms10004 (2015). 26643973 PMC4686651 Showed that SF3B1 mutations are initiating events in MDS. · DOI
  43. [51]Fabre MA The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606, 335– 342, doi: 10.1038/s41586-022-04785-z (2022). 35650444 PMC9177423 · DOI · Paper page
  44. [53]Ibrahimpasic T Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence. Clin Cancer Res 23, 5970– 5980, doi: 10.1158/1078-0432.CCR-17-1183 (2017). 28634282 PMC5626586 · DOI
  45. [54]Anczuków O & Krainer AR Splicing-factor alterations in cancers. RNA 22, 1285– 1301, doi: 10.1261/rna.057919.116 (2016). 27530828 PMC4986885 · DOI
  46. [55]Seiler M Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types. Cell Rep 23, 282– 296 e284, doi: 10.1016/j.celrep.2018.01.088 (2018). 29617667 PMC5933844 · DOI
  47. [56]Escobar-Hoyos LF Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer. Cancer Cell 38, 198– 211 e198, doi: 10.1016/j.ccell.2020.05.010 (2020). 32559497 PMC8028848 · DOI
  48. [57]Anczukow O The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol 19, 220– 228, doi: 10.1038/nsmb.2207 (2012). 22245967 PMC3272117 · DOI
  49. [58]Anczukow O SRSF1-Regulated Alternative Splicing in Breast Cancer. Mol Cell 60, 105– 117, doi: 10.1016/j.molcel.2015.09.005 (2015). 26431027 PMC4597910 · DOI
  50. [59]Park S Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis. Cell Rep 29, 2672– 2688 e2677, doi: 10.1016/j.celrep.2019.10.110 (2019). 31775037 PMC6936330 Identified the functional roles of individual SR proteins in breast cancer. · DOI
  51. [60]Karni R The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol 14, 185– 193, doi: 10.1038/nsmb1209 (2007). 17310252 PMC4595851 Landmark study showing that SRSF1 is a proto-oncoprotein. · DOI
  52. [62]Ghigna C Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell 20, 881– 890, doi: 10.1016/j.molcel.2005.10.026 (2005). 16364913 · DOI
  53. [63]Das S, Anczukow O, Akerman M & Krainer AR Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep 1, 110– 117, doi: 10.1016/j.celrep.2011.12.001 (2012). 22545246 PMC3334311 · DOI
  54. [64]De Miguel FJ Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer. Cancer Research 74, 1105– 1115, doi: 10.1158/0008-5472.can-13-1481 (2014). 24371231 · DOI
  55. [65]Michlewski G, Sanford JR & Caceres JF The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Mol Cell 30, 179– 189 (2008). 18439897
  56. [66]Karni R, Hippo Y, Lowe SW & Krainer AR The splicing-factor oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci U S A 105, 15323– 15327, doi: 10.1073/pnas.0801376105 (2008). 18832178 PMC2563124 · DOI
  57. [67]Sen S, Langiewicz M, Jumaa H & Webster NJ Deletion of serine/arginine-rich splicing factor 3 in hepatocytes predisposes to hepatocellular carcinoma in mice. Hepatology 61, 171– 183, doi: 10.1002/hep.27380 (2015). 25132062 PMC4280350 · DOI
  58. [68]Ajiro M, Jia R, Yang Y, Zhu J & Zheng ZM A genome landscape of SRSF3-regulated splicing events and gene expression in human osteosarcoma U2OS cells. Nucleic Acids Res 44, 1854– 1870, doi: 10.1093/nar/gkv1500 (2016). 26704980 PMC4770227 · DOI
  59. [69]Wang Z Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J Mol Cell Biol 4, 79– 87, doi: 10.1093/jmcb/mjr030 (2012). 22044881 PMC3493165 · DOI
  60. [70]Kurokawa K Downregulation of serine/arginine-rich splicing factor 3 induces G1 cell cycle arrest and apoptosis in colon cancer cells. Oncogene 33, 1407– 1417, doi: 10.1038/onc.2013.86 (2014). 23503458 · DOI
  61. [71]Jia R, Ajiro M, Yu L, McCoy P Jr. & Zheng ZM Oncogenic splicing factor SRSF3 regulates ILF3 alternative splicing to promote cancer cell proliferation and transformation. RNA 25, 630– 644, doi: 10.1261/rna.068619.118 (2019). 30796096 PMC6467003 · DOI
  62. [72]Freytag M Epithelial splicing regulatory protein 1 and 2 (ESRP1 and ESRP2) upregulation predicts poor prognosis in prostate cancer. BMC Cancer 20, 1220, doi: 10.1186/s12885-020-07682-8 (2020). 33339518 PMC7749503 · DOI
  63. [73]Gokmen-Polar Y Splicing factor ESRP1 controls ER-positive breast cancer by altering metabolic pathways. EMBO Rep 20, 46078, doi: 10.15252/embr.201846078 (2019). PMC6362360 30665944 · DOI
  64. [74]Shapiro IM An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet 7, 1002218, doi: 10.1371/journal.pgen.1002218 (2011). PMC3158048 21876675 · DOI
  65. [75]Munkley J Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. Elife 8, 47678, doi: 10.7554/eLife.47678 (2019). PMC6788855 31478829 · DOI
  66. [76]Ishii H Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. J Biol Chem 289, 27386– 27399, doi: 10.1074/jbc.M114.589432 (2014). 25143390 PMC4183779 · DOI
  67. [77]Bechara EG, Sebestyen E, Bernardis I, Eyras E & Valcarcel J RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Mol Cell 52, 720– 733, doi: 10.1016/j.molcel.2013.11.010 (2013). 24332178 Demonstrated the role of RBMs in tumorgenesis. · DOI
  68. [78]Rintala-Maki ND Expression of RBM5-related factors in primary breast tissue. J Cell Biochem 100, 1440– 1458, doi: 10.1002/jcb.21134 (2007). 17131366 · DOI
  69. [79]Inoue A RBM10: Structure, functions, and associated diseases. Gene 783, 145463, doi: 10.1016/j.gene.2021.145463 (2021). 33515724 PMC10445532 · DOI
  70. [80]Lu W QKI impairs self-renewal and tumorigenicity of oral cancer cells via repression of SOX2. Cancer Biol Ther 15, 1174– 1184, doi: 10.4161/cbt.29502 (2014). 24918581 PMC4128860 · DOI
  71. [81]Zong FY The RNA-binding protein QKI suppresses cancer-associated aberrant splicing. PLoS Genet 10, 1004289, doi: 10.1371/journal.pgen.1004289 (2014). PMC3983035 24722255 · DOI
  72. [82]Bandopadhayay P MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet 48, 273– 282, doi: 10.1038/ng.3500 (2016). 26829751 PMC4767685 · DOI
  73. [83]Shirakihara T TGF-beta regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J 30, 783– 795, doi: 10.1038/emboj.2010.351 (2011). 21224849 PMC3041949 · DOI
  74. [84]Warzecha CC An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J 29, 3286– 3300, doi: 10.1038/emboj.2010.195 (2010). 20711167 PMC2957203 Demonstrated the important role played by regulated splicing during EMT. · DOI · Paper page
  75. [85]Warzecha CC, Shen S, Xing Y & Carstens RP The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol 6, 546– 562 (2009). 19829082 PMC2823379
  76. [86]Yae T Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun 3, 883, doi: 10.1038/ncomms1892 (2012). 22673910 Demonstrated the role of a CD44 isoform in lung metastasis in vivo. · DOI
  77. [87]Sutherland LC, Wang K & Robinson AG RBM5 as a putative tumor suppressor gene for lung cancer. J Thorac Oncol 5, 294– 298, doi: 10.1097/JTO.0b013e3181c6e330 (2010). 20186023 · DOI
  78. [88]Jamsai D In vivo evidence that RBM5 is a tumour suppressor in the lung. Sci Rep 7, 16323, doi: 10.1038/s41598-017-15874-9 (2017). 29176597 PMC5701194 · DOI
  79. [89]Zhao Y The tumor suppressing effects of QKI-5 in prostate cancer: a novel diagnostic and prognostic protein. Cancer Biol Ther 15, 108– 118, doi: 10.4161/cbt.26722 (2014). 24153116 PMC3938513 · DOI
  80. [91]Jung H Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat Genet 47, 1242– 1248, doi: 10.1038/ng.3414 (2015). 26437032 · DOI
  81. [92]Mogilevsky M Modulation of MKNK2 alternative splicing by splice-switching oligonucleotides as a novel approach for glioblastoma treatment. Nucleic Acids Res 46, 11396– 11404, doi: 10.1093/nar/gky921 (2018). 30329087 PMC6265459 · DOI
  82. [93]Koh CM MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 523, 96– 100, doi: 10.1038/nature14351 (2015). 25970242 Identified a MYC-driven splicing vulnerability. · DOI
  83. [94]Ben-Hur V S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Rep 3, 103– 115, doi: 10.1016/j.celrep.2012.11.020 (2013). 23273915 PMC5021319 · DOI
  84. [95]Amaral CL S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells. BMC Cancer 16, 602, doi: 10.1186/s12885-016-2629-y (2016). 27491285 PMC4974797 · DOI
  85. [96]Mei H, Wang Y, Fan J & Lin Z Alternative splicing of S6K1 promotes non-small cell lung cancer survival. Tumour Biol 37, 13369– 13376, doi: 10.1007/s13277-016-5253-1 (2016). 27460085 · DOI
  86. [97]David CJ, Chen M, Assanah M, Canoll P & Manley JL HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463, 364– 368, doi: 10.1038/nature08697 (2010). 20010808 PMC2950088 · DOI · Paper page
  87. [98]Clower CV The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proc Natl Acad Sci U S A 107, 1894– 1899, doi: 10.1073/pnas.0914845107 (2010). 20133837 PMC2838216 · DOI · Paper page
  88. [99]Dayton TL, Jacks T & Vander Heiden MG PKM2, cancer metabolism, and the road ahead. EMBO Rep 17, 1721– 1730, doi: 10.15252/embr.201643300 (2016). 27856534 PMC5283597 · DOI · Paper page
  89. [100]Wang Z, Jeon HY, Rigo F, Bennett CF & Krainer AR Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides. Open Biol 2, 120133, doi: 10.1098/rsob.120133 (2012). 23155487 PMC3498831 · DOI
  90. [101]Boise LH bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597– 608, doi: 10.1016/0092-8674(93)90508-n (1993). 8358789 · DOI
  91. [102]Wu L, Mao C & Ming X Modulation of Bcl-x Alternative Splicing Induces Apoptosis of Human Hepatic Stellate Cells. Biomed Res Int 2016, 7478650, doi: 10.1155/2016/7478650 (2016). 27579319 PMC4992517 · DOI
  92. [103]Dole MG Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells. Cancer Res 56, 5734– 5740 (1996). 8971184
  93. [104]Minn AJ, Boise LH & Thompson CB Bcl-x(S) anatagonizes the protective effects of Bcl-x(L). J Biol Chem 271, 6306– 6312 (1996). 8626425
  94. [105]Paronetto MP, Achsel T, Massiello A, Chalfant CE & Sette C The RNA-binding protein Sam68 modulates the alternative splicing of Bcl-x. J Cell Biol 176, 929– 939, doi: 10.1083/jcb.200701005 (2007). 17371836 PMC2064079 · DOI
  95. [106]Zhou A, Ou AC, Cho A, Benz EJ Jr. & Huang SC Novel splicing factor RBM25 modulates Bcl-x pre-mRNA 5’ splice site selection. Mol Cell Biol 28, 5924– 5936, doi: 10.1128/MCB.00560-08 (2008). 18663000 PMC2546994 · DOI
  96. [107]Bielli P, Bordi M, Di Biasio V & Sette C Regulation of BCL-X splicing reveals a role for the polypyrimidine tract binding protein (PTBP1/hnRNP I) in alternative 5’ splice site selection. Nucleic Acids Res 42, 12070– 12081, doi: 10.1093/nar/gku922 (2014). 25294838 PMC4231771 · DOI
  97. [108]Wang Y The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer Cell 26, 374– 389, doi: 10.1016/j.ccr.2014.07.010 (2014). 25203323 PMC4159621 Demonstrated the role of RBMs in tumorgenesis in vivo. · DOI
  98. [109]Moore MJ, Wang Q, Kennedy CJ & Silver PA An alternative splicing network links cell-cycle control to apoptosis. Cell 142, 625– 636, doi: 10.1016/j.cell.2010.07.019 (2010). 20705336 PMC2924962 · DOI
  99. [110]Garneau D, Revil T, Fisette JF & Chabot B Heterogeneous nuclear ribonucleoprotein F/H proteins modulate the alternative splicing of the apoptotic mediator Bcl-x. J Biol Chem 280, 22641– 22650, doi: 10.1074/jbc.M501070200 (2005). 15837790 · DOI
  100. [111]Revil T, Pelletier J, Toutant J, Cloutier A & Chabot B Heterogeneous nuclear ribonucleoprotein K represses the production of pro-apoptotic Bcl-xS splice isoform. J Biol Chem 284, 21458– 21467, doi: 10.1074/jbc.M109.019711 (2009). 19520842 PMC2755870 · DOI
  101. [112]Cloutier P Antagonistic effects of the SRp30c protein and cryptic 5’ splice sites on the alternative splicing of the apoptotic regulator Bcl-x. J Biol Chem 283, 21315– 21324, doi: 10.1074/jbc.M800353200 (2008). 18534987 · DOI
  102. [113]Pabla N, Bhatt K & Dong Z Checkpoint kinase 1 (Chk1)-short is a splice variant and endogenous inhibitor of Chk1 that regulates cell cycle and DNA damage checkpoints. Proc Natl Acad Sci U S A 109, 197– 202, doi: 10.1073/pnas.1104767109 (2012). 22184239 PMC3252905 · DOI
  103. [114]Hu G Clinical and functional significance of CHK1-S, an alternatively spliced isoform of the CHK1 gene, in hepatocellular carcinoma. J Cancer 11, 1792– 1799, doi: 10.7150/jca.39443 (2020). 32194790 PMC7052871 · DOI
  104. [115]Wong MS, Shay JW & Wright WE Regulation of human telomerase splicing by RNA:RNA pairing. Nat Commun 5, 3306, doi: 10.1038/ncomms4306 (2014). 24577044 PMC3948165 · DOI
  105. [116]Sayed ME NOVA1 directs PTBP1 to hTERT pre-mRNA and promotes telomerase activity in cancer cells. Oncogene 38, 2937– 2952, doi: 10.1038/s41388-018-0639-8 (2019). 30568224 PMC6474811 · DOI
  106. [117]Ludlow AT NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer. Nat Commun 9, 3112, doi: 10.1038/s41467-018-05582-x (2018). 30082712 PMC6079032 · DOI
  107. [118]Listerman I, Sun J, Gazzaniga FS, Lukas JL & Blackburn EH The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis. Cancer Res 73, 2817– 2828, doi: 10.1158/0008-5472.CAN-12-3082 (2013). 23610451 PMC3643995 · DOI
  108. [119]Pont AR, Sadri N, Hsiao SJ, Smith S & Schneider RJ mRNA decay factor AUF1 maintains normal aging, telomere maintenance, and suppression of senescence by activation of telomerase transcription. Mol Cell 47, 5– 15, doi: 10.1016/j.molcel.2012.04.019 (2012). 22633954 PMC3966316 · DOI
  109. [120]Kang X, Chen W, Kim RH, Kang MK & Park NH Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. Oncogene 28, 565– 574, doi: 10.1038/onc.2008.404 (2009). 19015635 PMC2919678 · DOI
  110. [121]DiFeo A, Martignetti JA & Narla G The role of KLF6 and its splice variants in cancer therapy. Drug Resist Updat 12, 1– 7, doi: 10.1016/j.drup.2008.11.001 (2009). 19097929 · DOI
  111. [122]Hatami R KLF6-SV1 drives breast cancer metastasis and is associated with poor survival. Sci Transl Med 5, 12, doi: 10.1126/scitranslmed.3004688 (2013). PMC4661785 23345610 · DOI
  112. [123]Yea S Ras promotes growth by alternative splicing-mediated inactivation of the KLF6 tumor suppressor in hepatocellular carcinoma. Gastroenterology 134, 1521– 1531, doi: 10.1053/j.gastro.2008.02.015 (2008). 18471523 PMC2600656 · DOI
  113. [124]Botella LM TGF-beta regulates the expression of transcription factor KLF6 and its splice variants and promotes co-operative transactivation of common target genes through a Smad3-Sp1-KLF6 interaction. Biochem J 419, 485– 495, doi: 10.1042/BJ20081434 (2009). 19076057 PMC2882110 · DOI
  114. [125]DiFeo A A functional role for KLF6-SV1 in lung adenocarcinoma prognosis and chemotherapy response. Cancer Res 68, 965– 970, doi: 10.1158/0008-5472.CAN-07-2604 (2008). 18250346 PMC2826216 · DOI
  115. [126]Tanaka N, Yoshida H, Suzuki Y & Harigaya K Relative expression of hMena11a and hMenaINV splice isoforms is a useful biomarker in development and progression of human breast carcinoma. Int J Oncol 45, 1921– 1928, doi: 10.3892/ijo.2014.2591 (2014). 25109497 · DOI
  116. [127]Oudin MJ Characterization of the expression of the pro-metastatic Mena(INV) isoform during breast tumor progression. Clin Exp Metastasis 33, 249– 261, doi: 10.1007/s10585-015-9775-5 (2016). 26680363 PMC4777680 Characterized the expression of MENA isoforms in primary tumors. · DOI
  117. [128]Goswami S Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin Exp Metastasis 26, 153– 159, doi: 10.1007/s10585-008-9225-8 (2009). 18985426 PMC3042857 · DOI
  118. [129]Di Modugno F Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors. Proc Natl Acad Sci U S A 109, 19280– 19285, doi: 10.1073/pnas.1214394109 (2012). 23129656 PMC3511125 · DOI
  119. [130]Bria E Prognostic impact of alternative splicing-derived hMENA isoforms in resected, node-negative, non-small-cell lung cancer. Oncotarget 5, 11054– 11063, doi: 10.18632/oncotarget.2609 (2014). 25373410 PMC4294370 · DOI
  120. [131]Balsamo M The alternatively-included 11a sequence modifies the effects of Mena on actin cytoskeletal organization and cell behavior. Sci Rep 6, 35298, doi: 10.1038/srep35298 (2016). 27748415 PMC5066228 · DOI
  121. [132]Di Modugno F Molecular cloning of hMena (ENAH) and its splice variant hMena+11a: epidermal growth factor increases their expression and stimulates hMena+11a phosphorylation in breast cancer cell lines. Cancer Res 67, 2657– 2665, doi: 10.1158/0008-5472.CAN-06-1997 (2007). 17363586 PMC3156572 · DOI
  122. [133]Philippar U A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev Cell 15, 813– 828, doi: 10.1016/j.devcel.2008.09.003 (2008). 19081071 PMC2637261 Identified MENA isoforms. · DOI
  123. [134]Houck KA The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 5, 1806– 1814, doi: 10.1210/mend-5-12-1806 (1991). 1791831 · DOI
  124. [135]Bates DO VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down-regulated in renal cell carcinoma. Cancer Res 62, 4123– 4131 (2002). 12124351 Identified VEGF isoforms.
  125. [136]Woolard J VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 64, 7822– 7835, doi: 10.1158/0008-5472.CAN-04-0934 (2004). 15520188 · DOI · Paper page
  126. [137]Nowak DG Regulation of vascular endothelial growth factor (VEGF) splicing from pro-angiogenic to anti-angiogenic isoforms: a novel therapeutic strategy for angiogenesis. J Biol Chem 285, 5532– 5540, doi: 10.1074/jbc.M109.074930 (2010). 19906640 PMC2820781 · DOI
  127. [138]Harper SJ & Bates DO VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer 8, 880– 887, doi: 10.1038/nrc2505 (2008). 18923433 PMC2613352 · DOI
  128. [139]Pritchard-Jones RO Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma. Br J Cancer 97, 223– 230, doi: 10.1038/sj.bjc.6603839 (2007). 17595666 PMC2360298 · DOI
  129. [140]Varey AH VEGF 165 b, an antiangiogenic VEGF-A isoform, binds and inhibits bevacizumab treatment in experimental colorectal carcinoma: balance of pro- and antiangiogenic VEGF-A isoforms has implications for therapy. Br J Cancer 98, 1366– 1379, doi: 10.1038/sj.bjc.6604308 (2008). 18349829 PMC2361696 · DOI
  130. [141]Biselli-Chicote PM Overexpression of Antiangiogenic Vascular Endothelial Growth Factor Isoform and Splicing Regulatory Factors in Oral, Laryngeal and Pharyngeal Squamous Cell Carcinomas. Asian Pac J Cancer Prev 18, 2171– 2177, doi: 10.22034/APJCP.2017.18.8.2171 (2017). 28843252 PMC5697477 · DOI
  131. [142]Rennel E The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice. Br J Cancer 98, 1250– 1257, doi: 10.1038/sj.bjc.6604309 (2008). 18349828 PMC2359649 · DOI
  132. [143]Robertson C The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking. Exp Cell Res 343, 73– 81, doi: 10.1016/j.yexcr.2015.11.009 (2016). 26597760 · DOI · Paper page
  133. [145]Schiefner A, Gebauer M & Skerra A Extra-domain B in oncofetal fibronectin structurally promotes fibrillar head-to-tail dimerization of extracellular matrix protein. J Biol Chem 287, 17578– 17588, doi: 10.1074/jbc.M111.303131 (2012). 22442152 PMC3366777 · DOI
  134. [146]Fukuda T Mice lacking the EDB segment of fibronectin develop normally but exhibit reduced cell growth and fibronectin matrix assembly in vitro. Cancer Res 62, 5603– 5610 (2002). 12359774
  135. [147]Borsi L Expression of different tenascin isoforms in normal, hyperplastic and neoplastic human breast tissues. Int J Cancer 52, 688– 692 (1992). 1385335
  136. [148]Briones-Orta MA Osteopontin splice variants and polymorphisms in cancer progression and prognosis. Biochim Biophys Acta 1868, 93– 108 A, doi: 10.1016/j.bbcan.2017.02.005 (2017). 28254527 · DOI
  137. [149]Srebrow A, Blaustein M & Kornblihtt AR Regulation of fibronectin alternative splicing by a basement membrane-like extracellular matrix. FEBS Lett 514, 285– 289 (2002). 11943167
  138. [150]Bordeleau F Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors. Proc Natl Acad Sci U S A 112, 8314– 8319, doi: 10.1073/pnas.1505421112 (2015). 26106154 PMC4500261 · DOI
  139. [151]Martinez NM & Lynch KW Control of alternative splicing in immune responses: many regulators, many predictions, much still to learn. Immunol Rev 253, 216– 236, doi: 10.1111/imr.12047 (2013). 23550649 PMC3621013 · DOI
  140. [152]O’Connor BP Regulation of toll-like receptor signaling by the SF3a mRNA splicing complex. PLoS Genet 11, 1004932, doi: 10.1371/journal.pgen.1004932 (2015). PMC4450051 25658809 · DOI
  141. [153]Adib-Conquy M Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Crit Care Med 34, 2377– 2385, doi: 10.1097/01.CCM.0000233875.93866.88 (2006). 16850005 · DOI
  142. [154]De Arras L Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity. Genetics 197, 485– 496, doi: 10.1534/genetics.113.160499 (2014). 24361939 PMC4063909 · DOI
  143. [155]Poulikakos PI RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480, 387– 390, doi: 10.1038/nature10662 (2011). 22113612 PMC3266695 · DOI · Paper page
  144. [156]Wang Y The BRCA1-Delta11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Res 76, 2778– 2790, doi: 10.1158/0008-5472.CAN-16-0186 (2016). 27197267 PMC4874568 · DOI
  145. [157]Ozden O Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer. Sci Rep 6, 26273, doi: 10.1038/srep26273 (2016). 27197561 PMC4873788 · DOI
  146. [158]Ng KP A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 18, 521– 528, doi: 10.1038/nm.2713 (2012). 22426421 Linked resistance to tyrosine kinase inhibitors with BIM splicing. · DOI · Paper page
  147. [159]Castiglioni F Role of exon-16-deleted HER2 in breast carcinomas. Endocr Relat Cancer 13, 221– 232, doi: 10.1677/erc.1.01047 (2006). 16601290 · DOI
  148. [160]Alajati A Mammary tumor formation and metastasis evoked by a HER2 splice variant. Cancer Res 73, 5320– 5327, doi: 10.1158/0008-5472.CAN-12-3186 (2013). 23867476 · DOI
  149. [161]Dehm SM, Schmidt LJ, Heemers HV, Vessella RL & Tindall DJ Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res 68, 5469– 5477, doi: 10.1158/0008-5472.CAN-08-0594 (2008). 18593950 PMC2663383 Identified a constitutively active AR isoform that contributes to therapy resistance. · DOI · Paper page
  150. [162]Antonarakis ES AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 371, 1028– 1038, doi: 10.1056/NEJMoa1315815 (2014). 25184630 PMC4201502 · DOI · Paper page
  151. [163]Sun S Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120, 2715– 2730, doi: 10.1172/JCI41824 (2010). 20644256 PMC2912187 Identified a constitutively active AR isoform that contributes to castration resistance. · DOI · Paper page
  152. [164]Thiebaut C The Role of ERalpha36 in Development and Tumor Malignancy. Int J Mol Sci 21, 4116, doi: 10.3390/ijms21114116 (2020). 32526980 PMC7312586 · DOI
  153. [165]Zheng S, Asnani M & Thomas-Tikhonenko A Escape From ALL-CARTaz: Leukemia Immunoediting in the Age of Chimeric Antigen Receptors. Cancer J 25, 217– 222, doi: 10.1097/PPO.0000000000000381 (2019). 31135529 PMC6617517 · DOI
  154. [166]Sotillo E Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. Cancer Discov 5, 1282– 1295, doi: 10.1158/2159-8290.CD-15-1020 (2015). 26516065 PMC4670800 Demonstrated that alternative splicing can enable escape from CAR-T cell therapy. · DOI
  155. [167]Zheng S Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies. Blood Cancer Discovery 3, 103– 115, doi: 10.1158/2643-3230.bcd-21-0087 (2022). 35015683 PMC9780083 · DOI
  156. [168]Nakajima H New antitumor substances, FR901463, FR901464 and FR901465. II. Activities against experimental tumors in mice and mechanism of action. J Antibiot (Tokyo) 49, 1204– 1211, doi: 10.7164/antibiotics.49.1204 (1996). 9031665 · DOI
  157. [169]Thompson CF, Jamison TF & Jacobsen EN FR901464: total synthesis, proof of structure, and evaluation of synthetic analogues. J Am Chem Soc 123, 9974– 9983, doi: 10.1021/ja016615t (2001). 11592876 · DOI
  158. [170]Kaida D Spliceostatin A targets SF3b and inhibits both splicing and nuclear retention of pre-mRNA. Nat Chem Biol 3, 576– 583, doi: 10.1038/nchembio.2007.18 (2007). 17643111 · DOI
  159. [171]Osman S Structural requirements for the antiproliferative activity of pre-mRNA splicing inhibitor FR901464. Chemistry 17, 895– 904, doi: 10.1002/chem.201002402 (2011). 21226105 PMC3529175 · DOI
  160. [172]Albert BJ, Sivaramakrishnan A, Naka T, Czaicki NL & Koide K Total syntheses, fragmentation studies, and antitumor/antiproliferative activities of FR901464 and its low picomolar analogue. J Am Chem Soc 129, 2648– 2659, doi: 10.1021/ja067870m (2007). 17279752 PMC2530894 · DOI
  161. [173]Liu X Genomics-guided discovery of thailanstatins A, B, and C As pre-mRNA splicing inhibitors and antiproliferative agents from Burkholderia thailandensis MSMB43. J Nat Prod 76, 685– 693, doi: 10.1021/np300913h (2013). 23517093 PMC3696399 · DOI
  162. [174]Corrionero A, Minana B & Valcarcel J Reduced fidelity of branch point recognition and alternative splicing induced by the anti-tumor drug spliceostatin A. Genes Dev 25, 445– 459, doi: 10.1101/gad.2014311 (2011). 21363963 PMC3049286 Characterized the mechanism of action of spliceostatin A. · DOI
  163. [175]Seiler M H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med 24, 497– 504, doi: 10.1038/nm.4493 (2018). 29457796 PMC6730556 · DOI
  164. [176]Hong DS A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors. Invest New Drugs 32, 436– 444, doi: 10.1007/s10637-013-0046-5 (2014). 24258465 · DOI
  165. [177]Eskens FA Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors. Clin Cancer Res 19, 6296– 6304, doi: 10.1158/1078-0432.CCR-13-0485 (2013). 23983259 · DOI
  166. [178]Steensma DP Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia 35, 3542– 3550, doi: 10.1038/s41375-021-01328-9 (2021). 34172893 PMC8632688 · DOI
  167. [179]O’Brien K, Matlin AJ, Lowell AM & Moore MJ The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing. J Biol Chem 283, 33147– 33154, doi: 10.1074/jbc.M805556200 (2008). 18826947 PMC2586251 · DOI
  168. [180]Vanzyl EJ The spliceosome inhibitors isoginkgetin and pladienolide B induce ATF3-dependent cell death. PLoS One 15, e0224953, doi: 10.1371/journal.pone.0224953 (2020). 33370278 PMC7769279 · DOI
  169. [181]Yoon SO, Shin S, Lee HJ, Chun HK & Chung AS Isoginkgetin inhibits tumor cell invasion by regulating phosphatidylinositol 3-kinase/Akt-dependent matrix metalloproteinase-9 expression. Mol Cancer Ther 5, 2666– 2675, doi: 10.1158/1535-7163.MCT-06-0321 (2006). 17121913 · DOI
  170. [182]Darrigrand R Isoginkgetin derivative IP2 enhances the adaptive immune response against tumor antigens. Commun Biol 4, 269, doi: 10.1038/s42003-021-01801-2 (2021). 33649389 PMC7921396 · DOI
  171. [183]Han T Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, 3755, doi: 10.1126/science.aal3755 (2017). 28302793 Identified RBM39 as the molecular target of indisulam. · DOI · Paper page
  172. [184]Ting TC Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15. Cell Rep 29, 1499– 1510 e1496, doi: 10.1016/j.celrep.2019.09.079 (2019). 31693891 PMC7950731 · DOI · Paper page
  173. [185]Bussiere DE Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat Chem Biol 16, 15– 23, doi: 10.1038/s41589-019-0411-6 (2020). 31819272 · DOI · Paper page
  174. [186]Tari M U2AF(65) assemblies drive sequence-specific splice site recognition. EMBO Rep 20, 47604, doi: 10.15252/embr.201847604 (2019). PMC6681011 31271494 · DOI
  175. [187]Stepanyuk GA UHM-ULM interactions in the RBM39-U2AF65 splicing-factor complex. Acta Crystallogr D Struct Biol 72, 497– 511, doi: 10.1107/S2059798316001248 (2016). 27050129 PMC4822562 · DOI
  176. [188]Loerch S, Maucuer A, Manceau V, Green MR & Kielkopf CL Cancer-relevant splicing factor CAPERalpha engages the essential splicing factor SF3b155 in a specific ternary complex. J Biol Chem 289, 17325– 17337, doi: 10.1074/jbc.M114.558825 (2014). 24795046 PMC4067167 · DOI
  177. [189]Kralovicova J PUF60-activated exons uncover altered 3’ splice-site selection by germline missense mutations in a single RRM. Nucleic Acids Res 46, 6166– 6187, doi: 10.1093/nar/gky389 (2018). 29788428 PMC6093180 · DOI
  178. [190]Mai S Global regulation of alternative RNA splicing by the SR-rich protein RBM39. Biochim Biophys Acta 1859, 1014– 1024, doi: 10.1016/j.bbagrm.2016.06.007 (2016). 27354116 · DOI
  179. [191]Xu Y, Nijhuis A & Keun HC RNA-binding motif protein 39 (RBM39): An emerging cancer target. Br J Pharmacol 179, 2795– 2812, doi: 10.1111/bph.15331 (2020). 33238031 · DOI
  180. [192]Hamid O A randomized, open-label clinical trial of tasisulam sodium versus paclitaxel as second-line treatment in patients with metastatic melanoma. Cancer 120, 2016– 2024, doi: 10.1002/cncr.28635 (2014). 24676877 · DOI
  181. [193]Bezzi M Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev 27, 1903– 1916, doi: 10.1101/gad.219899.113 (2013). 24013503 PMC3778243 · DOI
  182. [194]Radzisheuskaya A PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia. Nat Struct Mol Biol 26, 999– 1012, doi: 10.1038/s41594-019-0313-z (2019). 31611688 PMC6858565 · DOI
  183. [195]Fong JY Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation. Cancer Cell 36, 194– 209 e199, doi: 10.1016/j.ccell.2019.07.003 (2019). 31408619 PMC7194031 · DOI
  184. [196]Gammons MV Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD. Invest Ophthalmol Vis Sci 54, 6052– 6062, doi: 10.1167/iovs.13-12422 (2013). 23887803 PMC3771558 · DOI
  185. [197]Hatcher JM SRPKIN-1: A Covalent SRPK1/2 Inhibitor that Potently Converts VEGF from Pro-angiogenic to Anti-angiogenic Isoform. Cell Chem Biol 25, 460– 470 e466, doi: 10.1016/j.chembiol.2018.01.013 (2018). 29478907 PMC5973797 · DOI
  186. [198]Batson J Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease. ACS Chem Biol 12, 825– 832, doi: 10.1021/acschembio.6b01048 (2017). 28135068 · DOI
  187. [199]Sakuma M, Iida K & Hagiwara M Deciphering targeting rules of splicing modulator compounds: case of TG003. BMC Mol Biol 16, 16, doi: 10.1186/s12867-015-0044-6 (2015). 26400733 PMC4580995 · DOI
  188. [200]Babu N Phosphoproteomic analysis identifies CLK1 as a novel therapeutic target in gastric cancer. Gastric Cancer 23, 796– 810, doi: 10.1007/s10120-020-01062-8 (2020). 32333232 · DOI
  189. [201]Uzor S CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer. Sci Rep 11, 7963, doi: 10.1038/s41598-021-86908-6 (2021). 33846420 PMC8041776 · DOI
  190. [202]Sohail M A novel class of inhibitors that target SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells. NAR Cancer 3, 19, doi: 10.1093/narcan/zcab019 (2021). PMC8210162 34316707 · DOI
  191. [203]Hluchy M CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1. Nature 609, 829– 834, doi: 10.1038/s41586-022-05204-z (2022). 36104565 · DOI
  192. [204]Sheridan C First small-molecule drug targeting RNA gains momentum. Nat Biotechnol 39, 6– 8, doi: 10.1038/s41587-020-00788-1 (2021). 33432225 · DOI
  193. [205]Baranello G Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med 384, 915– 923, doi: 10.1056/NEJMoa2009965 (2021). 33626251 Demonstrated that risdiplam increases SMN protein levels in patients with spinal muscular atrophy. · DOI
  194. [206]Sivaramakrishnan M Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nat Commun 8, 1476, doi: 10.1038/s41467-017-01559-4 (2017). 29133793 PMC5684323 · DOI
  195. [207]Costales MG, Childs-Disney JL, Haniff HS & Disney MD How We Think about Targeting RNA with Small Molecules. J Med Chem 63, 8880– 8900, doi: 10.1021/acs.jmedchem.9b01927 (2020). 32212706 PMC7486258 · DOI
  196. [208]Umuhire Juru A & Hargrove AE Frameworks for targeting RNA with small molecules. J Biol Chem 296, 100191, doi: 10.1074/jbc.REV120.015203 (2021). 33334887 PMC7948454 · DOI
  197. [209]Havens MA & Hastings ML Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res 44, 6549– 6563, doi: 10.1093/nar/gkw533 (2016). 27288447 PMC5001604 · DOI
  198. [210]Bennett CF & Swayze EE RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 50, 259– 293, doi: 10.1146/annurev.pharmtox.010909.105654 (2010). 20055705 · DOI
  199. [211]Kim Y Enhanced Potency of GalNAc-Conjugated Antisense Oligonucleotides in Hepatocellular Cancer Models. Mol Ther 27, 1547– 1557, doi: 10.1016/j.ymthe.2019.06.009 (2019). 31303442 PMC6731179 · DOI
  200. [212]Scharner J, Qi S, Rigo F, Bennett CF & Krainer AR Delivery of GalNAc-Conjugated Splice-Switching ASOs to Non-hepatic Cells through Ectopic Expression of Asialoglycoprotein Receptor. Mol Ther Nucleic Acids 16, 313– 325, doi: 10.1016/j.omtn.2019.02.024 (2019). 30965276 PMC6453860 · DOI

200 of 257 shown

Cited by

Sorted by citations

Authors
Bradley, R. K., & Anczuków, O.
Affiliations
  • Fred Hutch Cancer Center (US)
  • The Jackson Laboratory for Genomic Medicine (US)
Corresponding author
  • Bradley, Robert K.
  • Anczuków, Olga
ORCID
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2023-01-10
Volume
23
Issue
3
Pages
135-155
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/s41568-022-00541-7
PMC
PMC10132032
OpenAlex
W4315475728
Cited by
579
References
16
Citations by year
2026: 169 · 2025: 201 · 2024: 164 · 2023: 44 · 2022: 1
FWCI
15.74
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • National Institutes of Health (CA 034196)
  • National Heart, Lung, and Blood Institute (HL128239, R01HL128239, R01HL151651)
  • National Cancer Institute (CA-034196, R01CA251138, R01CA248317, P30CA034196)
  • National Institute of General Medical Sciences (R01GM138541)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
cancer hallmarks, carcinogenesis, alternative splicing, splicing mutation, splicing factors, metastasis, chemoresistance, immune evasion, tumor progression
MeSH terms
Cell Transformation, Neoplastic, Humans, Neoplasms, RNA Splicing, Alternative Splicing, Protein Isoforms, Carcinogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review