title: A network-based analysis of colon cancer splicing changes reveals a tumorigenesis-favoring regulatory pathway emanating from ELK1.
abstract: Splicing aberrations are prominent drivers of cancer, yet the regulatory pathways controlling them are mostly unknown. Here we develop a method that integrates physical interaction, gene expression, and alternative splicing data to construct the largest map of transcriptomic and proteomic interactions leading to cancerous splicing aberrations defined to date, and identify driver pathways therein. We apply our method to colon adenocarcinoma and non-small-cell lung carcinoma. By focusing on colon cancer, we reveal a novel tumor-favoring regulatory pathway involving the induction of the transcription factor MYC by the transcription factor ELK1, as well as the subsequent induction of the alternative splicing factor PTBP1 by both. We show that PTBP1 promotes specific RAC1,NUMB, and PKM splicing isoforms that are major triggers of colon tumorigenesis. By testing the pathway's activity in patient tumor samples, we find ELK1,MYC, and PTBP1 to be overexpressed in conjunction with oncogenic KRAS mutations, and show that these mutations increase ELK1 levels via the RAS-MAPK pathway. We thus illuminate, for the first time, a full regulatory pathway connecting prevalent cancerous mutations to functional tumor-inducing splicing aberrations. Our results demonstrate our method is applicable to different cancers to reveal regulatory pathways promoting splicing aberrations.
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Dror
authors: D
authors: Hollander
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Maya
authors: M
authors: Donyo
authors: Blavatnik School of Computer Science, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Nir
authors: N
authors: Atias
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Keren
authors: K
authors: Mekahel
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Zeev
authors: Z
authors: Melamed
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Sivan
authors: S
authors: Yannai
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Galit
authors: G
authors: Lev-Maor
authors: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel;
authors: Asaf
authors: A
authors: Shilo
authors: Department of Molecular Genetics, Weizmann Institute, Rehovot 76100, Israel;
authors: Schraga
authors: S
authors: Schwartz
authors: Department of Pathology, Sheba Medical Center, Ramat Gan 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors: Iris
authors: I
authors: Barshack
authors: Blavatnik School of Computer Science, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Roded
authors: R
authors: Sharan
authors: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;
authors: Gil
authors: G
authors: Ast
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019295:Computational Biology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012326:RNA Splicing; D015398:Signal Transduction; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; C117307:KRAS protein, human; C450006:PTBP1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D050807:ets-Domain Protein Elk-1; D038941:Polypyrimidine Tract-Binding Protein; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)