1932

Abstract

RNA splicing, the enzymatic process of removing segments of premature RNA to produce mature RNA, is a key mediator of proteome diversity and regulator of gene expression. Increased systematic sequencing of the genome and transcriptome of cancers has identified a variety of means by which RNA splicing is altered in cancer relative to normal cells. These findings, in combination with the discovery of recurrent change-of-function mutations in splicing factors in a variety of cancers, suggest that alterations in splicing are drivers of tumorigenesis. Greater characterization of altered splicing in cancer parallels increasing efforts to pharmacologically perturb splicing and early-phase clinical development of small molecules that disrupt splicing in patients with cancer. Here we review recent studies of global changes in splicing in cancer, splicing regulation of mitogenic pathways critical in cancer transformation, and efforts to therapeutically target splicing in cancer.

Keyword(s): RNASF3B1splicingSRSF2U2AF1ZRSR2
Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030617-050407
2019-03-04
2024-12-09
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/3/1/annurev-cancerbio-030617-050407.html?itemId=/content/journals/10.1146/annurev-cancerbio-030617-050407&mimeType=html&fmt=ahah

Literature Cited

  1. Agrawal AA, Yu L, Smith PG, Buonamici S 2018. Targeting splicing abnormalities in cancer. Curr. Opin. Genet. Dev. 48:67–74
    [Google Scholar]
  2. Agrawal S, Eng C 2006. Differential expression of novel naturally occurring splice variants of PTEN and their functional consequences in Cowden syndrome and sporadic breast cancer. Hum. Mol. Genet. 15:777–87
    [Google Scholar]
  3. Alsafadi S, Houy A, Battistella A, Popova T, Wassef M et al. 2016. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat. Commun. 7:10615
    [Google Scholar]
  4. Anczuków O, Rosenberg AZ, Akerman M, Das S, Zhan L et al. 2012. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat. Struct. Mol. Biol. 19:220–28
    [Google Scholar]
  5. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ et al. 2016. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–405
    [Google Scholar]
  6. Assi R, Kantarjian HM, Kadia TM, Pemmaraju N, Jabbour E et al. 2018. Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome. Cancer 124:2758–65
    [Google Scholar]
  7. Babic I, Anderson ES, Tanaka K, Guo D, Masui K et al. 2013. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab 17:1000–8
    [Google Scholar]
  8. Baitei EY, Zou M, Al-Mohanna F, Collison K, Alzahrani AS et al. 2009. Aberrant BRAF splicing as an alternative mechanism for oncogenic B-Raf activation in thyroid carcinoma. J. Pathol. 217:707–15
    [Google Scholar]
  9. Barash Y, Calarco JA, Gao W, Pan Q, Wang X et al. 2010. Deciphering the splicing code. Nature 465:53–59
    [Google Scholar]
  10. Bechara EG, Sebestyen E, Bernardis I, Eyras E, Valcarcel J 2013. RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Mol. Cell 52:720–33
    [Google Scholar]
  11. Ben-Hur V, Denichenko P, Siegfried Z, Maimon A, Krainer A et al. 2013. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Rep 3:103–15
    [Google Scholar]
  12. Carrocci TJ, Zoerner DM, Paulson JC, Hoskins AA 2017. SF3b1 mutations associated with myelodysplastic syndromes alter the fidelity of branchsite selection in yeast. Nucleic Acids Res 45:4837–52
    [Google Scholar]
  13. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO et al. 2012. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–4
    [Google Scholar]
  14. Chen L, Chen JY, Huang YJ, Gu Y, Qiu J et al. 2018. The augmented R-loop is a unifying mechanism for myelodysplastic syndromes induced by high-risk splicing factor mutations. Mol. Cell 69:412–25.e6
    [Google Scholar]
  15. Climente-Gonzalez H, Porta-Pardo E, Godzik A, Eyras E 2017. The functional impact of alternative splicing in cancer. Cell Rep 20:2215–26
    [Google Scholar]
  16. Clower CV, Chatterjee D, Wang Z, Cantley LC, Vander Heiden MG, Krainer AR 2010. The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. PNAS 107:1894–99
    [Google Scholar]
  17. Cohen-Eliav M, Golan-Gerstl R, Siegfried Z, Andersen CL, Thorsen K et al. 2013. The splicing factor SRSF6 is amplified and is an oncoprotein in lung and colon cancers. J. Pathol. 229:630–39
    [Google Scholar]
  18. Cretu C, Agrawal AA, Cook A, Will CL, Fekkes P et al. 2018. Structural basis of splicing modulation by antitumor macrolide compounds. Mol. Cell 70:265–73.e8
    [Google Scholar]
  19. Darman RB, Seiler M, Agrawal AA, Lim KH, Peng S et al. 2015. Cancer-associated SF3B1 hotspot mutations induce cryptic 3′ splice site selection through use of a different branch point. Cell Rep 13:1033–45
    [Google Scholar]
  20. Das S, Anczukow O, Akerman M, Krainer AR 2012. Oncogenic splicing factor SRSF1 is a critical transcriptional target of MYC. Cell Rep 1:110–17
    [Google Scholar]
  21. Dasgupta T, Ladd AN 2012. The importance of CELF control: molecular and biological roles of the CUG-BP, Elav-like family of RNA-binding proteins. WIREs RNA 3:104–21
    [Google Scholar]
  22. Daubner GM, Clery A, Jayne S, Stevenin J, Allain FH 2012. A syn-anti conformational difference allows SRSF2 to recognize guanines and cytosines equally well. EMBO J 31:162–74
    [Google Scholar]
  23. David CJ, Chen M, Assanah M, Canoll P, Manley JL 2010. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463:364–68
    [Google Scholar]
  24. DeBoever C, Ghia EM, Shepard PJ, Rassenti L, Barrett CL et al. 2015. Transcriptome sequencing reveals potential mechanism of cryptic 3′ splice site selection in SF3B1-mutated cancers. PLOS Comput. Biol. 11:e1004105
    [Google Scholar]
  25. Dittrich C, Dumez H, Calvert H, Hanauske A, Faber M et al. 2003. Phase I and pharmacokinetic study of E7070, a chloroindolyl-sulfonamide anticancer agent, administered on a weekly schedule to patients with solid tumors. Clin. Cancer Res. 9:5195–204
    [Google Scholar]
  26. Dvinge H, Kim E, Abdel-Wahab O, Bradley RK 2016. RNA splicing factors as oncoproteins and tumour suppressors. Nat. Rev. Cancer 16:413–30
    [Google Scholar]
  27. Eskens FA, Ramos FJ, Burger H, O'Brien JP, Piera A et al. 2013. Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors. Clin. Cancer Res. 19:6296–304
    [Google Scholar]
  28. Fica SM, Nagai K 2017. Cryo-electron microscopy snapshots of the spliceosome: structural insights into a dynamic ribonucleoprotein machine. Nat. Struct. Mol. Biol. 24:791–99
    [Google Scholar]
  29. Finci LI, Zhang X, Huang X, Zhou Q, Tsai J et al. 2018. The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action. Genes Dev 32:309–20
    [Google Scholar]
  30. Frampton GM, Ali SM, Rosenzweig M, Chmielecki J, Lu X et al. 2015. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 5:850–59
    [Google Scholar]
  31. Fu XD, Ares M 2014. Context-dependent control of alternative splicing by RNA-binding proteins. Nat. Rev. Genet. 15:689–701
    [Google Scholar]
  32. Furney SJ, Pedersen M, Gentien D, Dumont AG, Rapinat A et al. 2013. SF3B1 mutations are associated with alternative splicing in uveal melanoma. Cancer Discov 3:1122–29
    [Google Scholar]
  33. Goncalves V, Pereira JFS, Jordan P 2017. Signaling pathways driving aberrant splicing in cancer cells. Genes 9:9
    [Google Scholar]
  34. Graubert TA, Shen D, Ding L, Okeyo-Owuor T, Lunn CL et al. 2012. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet. 44:53–57
    [Google Scholar]
  35. Han T, Goralski M, Gaskill N, Capota E, Kim J et al. 2017. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356:eaal3755
    [Google Scholar]
  36. Harbour JW, Roberson ED, Anbunathan H, Onken MD, Worley LA, Bowcock AM 2013. Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma. Nat. Genet. 45:133–35
    [Google Scholar]
  37. Hernandez J, Bechara E, Schlesinger D, Delgado J, Serrano L, Valcarcel J 2016. Tumor suppressor properties of the splicing regulatory factor RBM10. RNA Biol 13:466–72
    [Google Scholar]
  38. Hollander D, Donyo M, Atias N, Mekahel K, Melamed Z et al. 2016. A network-based analysis of colon cancer splicing changes reveals a tumorigenesis-favoring regulatory pathway emanating from ELK1. Genome Res 26:541–53
    [Google Scholar]
  39. Hong DS, Kurzrock R, Naing A, Wheler JJ, Falchook GS et al. 2014. 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. Investig. New Drugs 32:436–44
    [Google Scholar]
  40. Hsu TY, Simon LM, Neill NJ, Marcotte R, Sayad A et al. 2015. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525:384–88
    [Google Scholar]
  41. Ibrahimpasic T, Xu B, Landa I, Dogan S, Middha S et al. 2017. 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. 23:5970–80
    [Google Scholar]
  42. Ilagan JO, Ramakrishnan A, Hayes B, Murphy ME, Zebari AS et al. 2015. U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Res 25:14–26
    [Google Scholar]
  43. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ et al. 2012. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107–20
    [Google Scholar]
  44. Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM et al. 2013. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397–409
    [Google Scholar]
  45. Jayasinghe RG, Cao S, Gao Q, Wendl MC, Vo NS et al. 2018. Systematic analysis of splice-site-creating mutations in cancer. Cell Rep 23:270–81.e3
    [Google Scholar]
  46. Jensen MA, Wilkinson JE, Krainer AR 2014. Splicing factor SRSF6 promotes hyperplasia of sensitized skin. Nat. Struct. Mol. Biol. 21:189–97
    [Google Scholar]
  47. Jia R, Li C, McCoy JP, Deng C-X, Zheng Z-M 2010. SRp20 is a proto-oncogene critical for cell proliferation and tumor induction and maintenance. Int. J. Biol. Sci. 6:806–26
    [Google Scholar]
  48. Jung H, Lee D, Lee J, Park D, Kim YJ et al. 2015. Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat. Genet. 47:1242–48
    [Google Scholar]
  49. Jurica MS, Moore MJ 2003. Pre-mRNA splicing: awash in a sea of proteins. Mol. Cell 12:5–14
    [Google Scholar]
  50. Kahles A, Lehmann K-V, Toussaint NC, Huser M, Stark SG et al. 2018. Comprehensive analysis of alternative splicing across tumors from 8,512 patients. Cell 34:211–224.e6
    [Google Scholar]
  51. Karni R, de Stanchina E, Lowe S, Sinha R, Mu D, Krainer A 2007. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat. Struct. Mol. Biol. 14:185–93
    [Google Scholar]
  52. Karni R, Hippo Y, Lowe SW, Krainer AR 2008. The splicing-factor oncoprotein SF2/ASF activates mTORC1. PNAS 105:15323–27
    [Google Scholar]
  53. Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC et al. 2015. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell 27:617–30
    [Google Scholar]
  54. Koh CM, Bezzi M, Low DH, Ang WX, Teo SX et al. 2015. MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature 523:96–100
    [Google Scholar]
  55. Konieczny P, Stepniak-Konieczna E, Sobczak K 2014. MBNL proteins and their target RNAs, interaction and splicing regulation. Nucleic Acids Res 42:10873–87
    [Google Scholar]
  56. Krecic AM, Swanson MS 1999. hnRNP complexes: composition, structure, and function. Curr. Opin. Cell Biol. 11:363–71
    [Google Scholar]
  57. Lee SC-W, Abdel-Wahab O 2016. Therapeutic targeting of splicing in cancer. Nat. Med. 22:976–86
    [Google Scholar]
  58. Lee SC-W, Dvinge H, Kim E, Cho H, Micol J-B et al. 2016.a Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat. Med. 22:672–78 Erratum. 2016. Nat. Med. 22:692
    [Google Scholar]
  59. Lee SC-W, Khrystyna D, Obeng EA, Kim E, Micol J-B, Yoshimi A et al. 2016.b Synthetic lethal interactions of MDS-associated spliceosomal gene mutations identifies the basis for their mutual exclusivity. Blood 128:961
    [Google Scholar]
  60. Loerch S, Maucuer A, Manceau V, Green MR, Kielkopf CL 2014. Cancer-relevant splicing factor CAPERα engages the essential splicing factor SF3b155 in a specific ternary complex. J. Biol. Chem. 289:17325–37
    [Google Scholar]
  61. Long JC, Caceres JF 2009. The SR protein family of splicing factors: master regulators of gene expression. Biochem. J. 417:15–27
    [Google Scholar]
  62. Madan V, Kanojia D, Li J, Okamoto R, Sato-Otsubo A et al. 2015. Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome. Nat. Commun. 6:6042
    [Google Scholar]
  63. Maimon A, Mogilevsky M, Shilo A, Golan-Gerstl R, Obiedat A et al. 2014. Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation. Cell Rep 7:501–13
    [Google Scholar]
  64. Martin M, Masshofer L, Temming P, Rahmann S, Metz C et al. 2013. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat. Genet. 45:933–36
    [Google Scholar]
  65. Mupo A, Seiler M, Sathiaseelan V, Pance A, Yang Y et al. 2017. Hemopoietic-specific Sf3b1-K700E knock-in mice display the splicing defect seen in human MDS but develop anemia without ring sideroblasts. Leukemia 31:720–27
    [Google Scholar]
  66. Nguyen HD, Yadav T, Giri S, Saez B, Graubert TA, Zou L 2017. Functions of replication protein A as a sensor of R loops and a regulator of RNaseH1. Mol. Cell 65:832–47.e4
    [Google Scholar]
  67. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN et al. 1994. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. PNAS 91:7727–31
    [Google Scholar]
  68. Obeng EA, Chappell RJ, Seiler M, Chen MC, Campagna DR et al. 2016. Physiologic expression of Sf3b1K700E causes impaired erythropoiesis, aberrant splicing, and sensitivity to therapeutic spliceosome modulation. Cancer Cell 30:404–17
    [Google Scholar]
  69. Panasyuk G, Nemazanyy I, Zhyvoloup A, Filonenko V, Davies D et al. 2009. mTORβ splicing isoform promotes cell proliferation and tumorigenesis. J. Biol. Chem. 284:30807–14
    [Google Scholar]
  70. Paolella BR, Gibson WJ, Urbanski LM, Alberta JA, Zack TI et al. 2017. Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability. eLife 6:e23268
    [Google Scholar]
  71. Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P et al. 2011. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 365:1384–95
    [Google Scholar]
  72. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G et al. 2013. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122:3616–27
    [Google Scholar]
  73. Papin C, Denouel-Galy A, Laugier D, Calothy G, Eychene A 1998. Modulation of kinase activity and oncogenic properties by alternative splicing reveals a novel regulatory mechanism for B-Raf. J. Biol. Chem. 273:24939–47
    [Google Scholar]
  74. Park SM, Ou J, Chamberlain L, Simone TM, Yang H et al. 2016. U2AF35(S34F) promotes transformation by directing aberrant ATG7 pre-mRNA 3′ end formation. Mol. Cell 62:479–90
    [Google Scholar]
  75. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C et al. 2011. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–90
    [Google Scholar]
  76. Quesada V, Conde L, Villamor N, Ordóñez G, Jares P et al. 2012. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat. Genet. 44:47–52
    [Google Scholar]
  77. Rauch J, Moran-Jones K, Albrecht V, Schwarzl T, Hunter K et al. 2011. c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway. Cancer Res 71:4664–74
    [Google Scholar]
  78. Ren J, Wen L, Gao X, Jin C, Xue Y, Yao X 2009. DOG 1.0: illustrator of protein domain structures. Cell Res 19:271–73
    [Google Scholar]
  79. Robertson AG, Shih J, Yau C, Gibb EA, Oba J et al. 2017. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell 32:204–20.e15
    [Google Scholar]
  80. Roy R, Huang Y, Seckl MJ, Pardo OE 2017. Emerging roles of hnRNPA1 in modulating malignant transformation. WIREs RNA 8:e1431
    [Google Scholar]
  81. Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC et al. 2003. The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization. Mol. Cell Biol. 23:5692–705
    [Google Scholar]
  82. Scheres SH, Nagai K 2017. CryoEM structures of spliceosomal complexes reveal the molecular mechanism of pre-mRNA splicing. Curr. Opin. Struct. Biol. 46:130–39
    [Google Scholar]
  83. Scotti MM, Swanson MS 2016. RNA mis-splicing in disease. Nat. Rev. Genet. 17:19–32
    [Google Scholar]
  84. Seiler M, Peng S, Agrawal AA, Palacino J, Teng T et al. 2018.a Somatic mutational landscape of splicing factor genes and their functional consequences across 33 cancer types. Cell Rep 23:282–96.e4
    [Google Scholar]
  85. Seiler M, Yoshimi A, Darman R, Chan B, Keaney G et al. 2018.b H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat. Med. 24:497–504
    [Google Scholar]
  86. Shi Y. 2017. Mechanistic insights into precursor messenger RNA splicing by the spliceosome. Nat. Rev. Mol. Cell Biol. 18:655–70
    [Google Scholar]
  87. Shilo A, Ben Hur V, Denichenko P, Stein I, Pikarsky E et al. 2014. Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development. RNA 20:505–15
    [Google Scholar]
  88. Shirai CL, White BS, Tripathi M, Tapia R, Ley JN et al. 2017. Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome. Nat. Commun. 8:14060
    [Google Scholar]
  89. Siegfried Z, Bonomi S, Ghigna C, Karni R 2013. Regulation of the Ras-MAPK and PI3K-mTOR signalling pathways by alternative splicing in cancer. Int. J. Cell Biol. 2013:568931
    [Google Scholar]
  90. Stepanyuk GA, Serrano P, Peralta E, Farr CL, Axelrod HL et al. 2016. UHM–ULM interactions in the RBM39–U2AF65 splicing-factor complex. Acta Crystallogr. D 72:497–511
    [Google Scholar]
  91. Sugawa N, Ekstrand AJ, James CD, Collins VP 1990. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. PNAS 87:8602–6
    [Google Scholar]
  92. Supek F, Minana B, Valcarcel J, Gabaldon T, Lehner B 2014. Synonymous mutations frequently act as driver mutations in human cancers. Cell 156:1324–35
    [Google Scholar]
  93. Sutherland LC, Rintala-Maki ND, White RD, Morin CD 2005. RNA binding motif (RBM) proteins: A novel family of apoptosis modulators. J. Cell Biochem. 94:5–24
    [Google Scholar]
  94. Takahashi H, Nishimura J, Kagawa Y, Kano Y, Takahashi Y et al. 2015. Significance of polypyrimidine tract-binding protein 1 expression in colorectal cancer. Mol. Cancer Ther. 14:1705–16
    [Google Scholar]
  95. Talbot DC, von Pawel J, Cattell E, Yule SM, Johnston C et al. 2007. A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer. Clin. Cancer Res. 13:1816–22
    [Google Scholar]
  96. Tang Q, Rodriguez-Santiago S, Wang J, Pu J, Yuste A et al. 2016. SF3B1/Hsh155 HEAT motif mutations affect interaction with the spliceosomal ATPase Prp5, resulting in altered branch site selectivity in pre-mRNA splicing. Genes Dev 30:2710–23
    [Google Scholar]
  97. Tang Y, Horikawa I, Ajiro M, Robles AI, Fujita K et al. 2013. Downregulation of splicing factor SRSF3 induces p53β, an alternatively spliced isoform of p53 that promotes cellular senescence. Oncogene 32:2792–2792
    [Google Scholar]
  98. Teng T, Tsai JH, Puyang X, Seiler M, Peng S et al. 2017. Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex. Nat. Commun. 8:15522
    [Google Scholar]
  99. Tsai FD, Lopes MS, Zhou M, Court H, Ponce O et al. 2015. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. PNAS 112:779–84
    [Google Scholar]
  100. Uehara T, Minoshima Y, Sagane K, Sugi NH, Mitsuhashi KO et al. 2017. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol. 13:675–80
    [Google Scholar]
  101. Ule J, Stefani G, Mele A, Ruggiu M, Wang X et al. 2006. An RNA map predicting Nova-dependent splicing regulation. Nature 444:580–86
    [Google Scholar]
  102. Valacca C, Bonomi S, Buratti E, Pedrotti S, Baralle FE et al. 2010. Sam68 regulates EMT through alternative splicing–activated nonsense-mediated mRNA decay of the SF2/ASF proto-oncogene. J. Cell Biol. 191:87–99
    [Google Scholar]
  103. Wahl MC, Luhrmann R 2015.a SnapShot: spliceosome dynamics I. Cell 161:1474.e1
    [Google Scholar]
  104. Wahl MC, Luhrmann R 2015.b SnapShot: spliceosome dynamics II. Cell 162:456.e1
    [Google Scholar]
  105. Wang H, Zhou M, Shi B, Zhang Q, Jiang H et al. 2011. Identification of an exon 4-deletion variant of epidermal growth factor receptor with increased metastasis-promoting capacity. Neoplasia 13:461–71
    [Google Scholar]
  106. Wang L, Lawrence M, Wan Y, Stojanov P, Sougnez C et al. 2011. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N. Engl. J. Med. 365:2497–506
    [Google Scholar]
  107. Weidle UH, Maisel D, Klostermann S, Weiss EH, Schmitt M 2011. Differential splicing generates new transmembrane receptor and extracellular matrix-related targets for antibody-based therapy of cancer. Cancer Genom. Proteom. 8:211–26
    [Google Scholar]
  108. Yamauchi T, Masuda T, Canver MC, Seiler M, Semba Y et al. 2018. Genome-wide CRISPR-Cas9 screen identifies leukemia-specific dependence on a pre-mRNA metabolic pathway regulated by DCPS. Cancer Cell 33:386–400.e5
    [Google Scholar]
  109. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y et al. 2011. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478:64–69
    [Google Scholar]
  110. Zhang J, Lieu YK, Ali AM, Penson A, Reggio KS et al. 2015. Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities. PNAS 112:E4726–34
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030617-050407
Loading
/content/journals/10.1146/annurev-cancerbio-030617-050407
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error