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A network-based analysis of colon cancer splicing changes reveals a tumorigenesis-favoring regulatory pathway

Dror Hollander1, Maya Donyo1, Nir Atias2

  • 1Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel;

Genome Research
|February 11, 2016
PubMed

Insights

This study maps cancer-driving splicing aberrations, revealing a novel pathway in colon cancer where ELK1 induces MYC, which then induces PTBP1. This pathway connects mutations to tumor-promoting splicing changes.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genomics

Background:

  • Splicing aberrations are key cancer drivers, but their regulatory mechanisms remain largely unknown.
  • Understanding these pathways is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To develop a method for mapping transcriptomic and proteomic interactions driving cancer-associated splicing aberrations.
  • To identify novel regulatory pathways involved in colon adenocarcinoma and non-small-cell lung carcinoma.

Main Methods:

  • Integration of physical interaction, gene expression, and alternative splicing data.
  • Application of the developed method to colon adenocarcinoma and non-small-cell lung carcinoma datasets.
  • Analysis of patient tumor samples to validate pathway activity and correlations with mutations.

Main Results:

  • A novel tumor-promoting pathway identified in colon cancer involving ELK1, MYC, and PTBP1.
  • PTBP1 was shown to induce specific splicing isoforms of RAC1, NUMB, and PKM, promoting tumorigenesis.
  • ELK1, MYC, and PTBP1 overexpression correlates with oncogenic KRAS mutations, which upregulate ELK1 via the RAS-MAPK pathway.

Conclusions:

  • The study elucidates a complete regulatory pathway linking common cancer mutations to functional, tumor-inducing splicing aberrations.
  • The developed method is effective for uncovering splicing aberration regulatory pathways across different cancer types.
  • This research provides new insights into the molecular mechanisms of cancer development and potential therapeutic targets.

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