Format

Send to

Choose Destination
Oncotarget. 2018 Jul 27;9(58):31214-31230. doi: 10.18632/oncotarget.25781. eCollection 2018 Jul 27.

Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.

Author information

1
Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, Ohio, United States of America.
2
Department of Pathology, Duke University School of Medicine, Durham, North Carolina, United States of America.
3
Biomedical Informatics Shared Resource, The Ohio State University, Columbus, Ohio, United States of America.
4
Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China.
5
Division of Bioinformatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
6
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
7
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.

Abstract

Mutation of the APC gene occurs in a high percentage of colorectal tumors and is a central event driving tumor initiation in the large intestine. The APC protein performs multiple tumor suppressor functions including negative regulation of the canonical WNT signaling pathway by both cytoplasmic and nuclear mechanisms. Published reports that APC interacts with β-catenin in the chromatin fraction to repress WNT-activated targets have raised the possibility that chromatin-associated APC participates more broadly in mechanisms of transcriptional control. This screening study has used chromatin immunoprecipitation and next-generation sequencing to identify APC-associated genomic regions in colon cancer cell lines. Initial target selection was performed by comparison and statistical analysis of 3,985 genomic regions associated with the APC protein to whole transcriptome sequencing data from APC-deficient and APC-wild-type colon cancer cells, and two types of murine colon adenomas characterized by activated Wnt signaling. 289 transcripts altered in expression following APC loss in human cells were linked to APC-associated genomic regions. High-confidence targets additionally validated in mouse adenomas included 16 increased and 9 decreased in expression following APC loss, indicating that chromatin-associated APC may antagonize canonical WNT signaling at both WNT-activated and WNT-repressed targets. Motif analysis and comparison to ChIP-seq datasets for other transcription factors identified a prevalence of binding sites for the TCF7L2 and AP-1 transcription factors in APC-associated genomic regions. Our results indicate that canonical WNT signaling can collaborate with or antagonize the AP-1 transcription factor to fine-tune the expression of shared target genes in the colorectal epithelium. Future therapeutic strategies for APC-deficient colorectal cancers might be expanded to include agents targeting the AP-1 pathway.

KEYWORDS:

AP-1; APC; canonical WNT signaling; chromatin; colorectal cancer

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center