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 tumorinducing splicing aberrations. Our results demonstrate our method is applicable to different cancers to reveal regulatory pathways promoting splicing aberrations.
Original language | American English |
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Pages (from-to) | 541-553 |
Number of pages | 13 |
Journal | Genome Research |
Volume | 26 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2016 |
Externally published | Yes |
Bibliographical note
Funding Information:We thank Ran Elkon, Carmit Levy, Noam Shomron, and Rotem Karni for helpful discussions. We thank Nir Kfir for his help in preparing Figure 1B. G.A. was supported by grants from the Israel Science Foundation (ISF 61/09 and ISF 142/13). R.S. was supported by grants from the Israel Science Foundation (241/11 and I-CORE 757/12). D.H. and N.A. were partially supported by a fellowship of the Edmond J. Safra Bioinformatics Center at Tel Aviv University.
Publisher Copyright:
© 2016 Hollander et al.