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

Publication ,  Journal Article
Hankey, W; Chen, Z; Bergman, MJ; Fernandez, MO; Hancioglu, B; Lan, X; Jegga, AG; Zhang, J; Jin, VX; Aronow, BJ; Wang, Q; Groden, J
Published in: Oncotarget
July 27, 2018

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.

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Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

July 27, 2018

Volume

9

Issue

58

Start / End Page

31214 / 31230

Location

United States

Related Subject Headings

  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hankey, W., Chen, Z., Bergman, M. J., Fernandez, M. O., Hancioglu, B., Lan, X., … Groden, J. (2018). Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1. Oncotarget, 9(58), 31214–31230. https://doi.org/10.18632/oncotarget.25781
Hankey, William, Zhong Chen, Maxwell J. Bergman, Max O. Fernandez, Baris Hancioglu, Xun Lan, Anil G. Jegga, et al. “Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.Oncotarget 9, no. 58 (July 27, 2018): 31214–30. https://doi.org/10.18632/oncotarget.25781.
Hankey W, Chen Z, Bergman MJ, Fernandez MO, Hancioglu B, Lan X, et al. Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1. Oncotarget. 2018 Jul 27;9(58):31214–30.
Hankey, William, et al. “Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1.Oncotarget, vol. 9, no. 58, July 2018, pp. 31214–30. Pubmed, doi:10.18632/oncotarget.25781.
Hankey W, Chen Z, Bergman MJ, Fernandez MO, Hancioglu B, Lan X, Jegga AG, Zhang J, Jin VX, Aronow BJ, Wang Q, Groden J. Chromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1. Oncotarget. 2018 Jul 27;9(58):31214–31230.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

July 27, 2018

Volume

9

Issue

58

Start / End Page

31214 / 31230

Location

United States

Related Subject Headings

  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis