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 tumorinducing splicing aberrations. Our results demonstrate our method is applicable to different cancers to reveal regulatory pathways promoting splicing aberrations.

PRPF overexpression induces drug resistance through actin cytoskeleton rearrangement and epithelial-mesenchymal transition

“…A network-based analysis of colon cancer splicing changes reported noteworthy differences in the induction of various transcription factors such as MYC and ELK1 [ 11 ], and supported our findings with respect to the activation of signaling pathways upon PRPF overexpression (Figure 2B ). ELK1 transcription is induced by mutant k-RAS through the RAS-MAPK pathway [ 11 ], and that is consistent with our observation of an increase in the activity of the RAS-ERK pathway following PRPF overexpression (Figure 2B ). PRPF overexpression may induce changes in splicing patterns, rescuing cell death, partly by inhibiting the generation of resveratrol-induced ROS, and regulating various cell survival signaling pathways (Figures 1C, D and 2A ).…”

“…In particular, PRPF6, a member of the small ribonucleoprotein complex, was shown to promote colon cancer proliferation [ 9 ]. Recent studies reported that changes in the pattern of various alternative splicing events play prominent roles in colon cancer carcinogenesis and tumorigenesis [ 10 – 11 ]. Different splicing patterns have been observed for several alternative splicing events in colon cancers when compared to the patterns in normal tissues; among these, the inclusion of the Rac1 3b exon is the most noteworthy, because it specifically contributes to colon tumorigenesis through genomic instability and EMT [ 12 – 13 ].…”

Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways

“…It has been reported that ERKs can activate several downstream transcription factors through phosphorylation to control the expression of specific genes [28]. Elk-1 is one of those downstream transcription factors [29]. In our study, we confirmed that inhibition of the ERK pathway leads to the downregulation of pElk-1, which is accompanied by the suppression of Snail.…”

Integrated analysis of the functions and prognostic values of RNA binding proteins in colon adenocarcinoma

“…The DOWN-DE-RBPs were signi cantly enriched for regulation of mRNA processing, regulation of mRNA metabolic process, RNA splicing, and mRNA 3'-UTR binding. Previous experiments have shown that RNA splicing, processing, localization, transport, and stability are directly related to the occurrence of COAD [19,20]. Circular RNAs (circRNAs) and micro RNAs (miRNAs) are the most common products of RNA splicing, and a large number of studies have also shown that they play an important role in the occurrence of COAD [21][22][23][24].…”