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Updated: Jun 11, 2025

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

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APC mutations dysregulate alternative polyadenylation in cancer

Austin M Gabel1,2,3,4, Andrea E Belleville1,2,3,5, James D Thomas1,2

  • 1Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Genome Biology
|October 7, 2024
PubMed
Abstract

Insights

Loss of the APC gene disrupts alternative polyadenylation (APA) in colorectal cancer, leading to widespread gene expression changes. This finding reveals a new mechanism driving cancer development.

Area of Science:

  • Genomics
  • Molecular Biology
  • Cancer Research

Background:

  • Alternative polyadenylation (APA) is a common gene regulation mechanism affecting most human genes.
  • APA dysregulation is a hallmark of many cancers, but its underlying causes are not fully understood.

Purpose of the Study:

  • To investigate the molecular regulators of poly(A) site selection across various cancer types.
  • To understand the specific role of Adenomatous Polyposis Coli (APC) mutations in APA dysregulation, particularly in colorectal adenocarcinoma.

Main Methods:

  • Unbiased analysis of poly(A) site selection regulators using The Cancer Genome Atlas (TCGA) data.
  • Comparative analysis of APA in colorectal adenocarcinoma versus other cancer subtypes.
  • Experimental validation using human colon organoids with APC knockout.
  • Bioinformatic analysis of existing APC eCLIP data to identify binding motifs.

Main Results:

  • Colorectal adenocarcinoma exhibits distinct APA patterns compared to other cancers, linked to frequent APC loss-of-function mutations.
  • APC mutations are associated with longer 3' UTR expression, indicating a shift towards distal polyadenylation site usage.
  • APC knockout in colon organoids recapitulates APA dysregulation observed in tumors.
  • APC protein preferentially binds G- and C-rich motifs upstream of proximal poly(A) sites.
  • Reduced APC expression correlates with APA dysregulation even in cancers without recurrent APC mutations.

Conclusions:

  • APC acts as a regulator of proximal poly(A) site usage.
  • APC loss or altered expression contributes significantly to the pervasive APA dysregulation observed in various cancers.
  • These findings highlight APC's role in maintaining normal gene expression through APA regulation and its implications in cancer pathogenesis.

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