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

dc.contributor.authorHankey, William
dc.contributor.authorChen, Zhong
dc.contributor.authorBergman, Maxwell J.
dc.contributor.authorFernandez, Max O.
dc.contributor.authorHancioglu, Baris
dc.contributor.authorLan, Xun
dc.contributor.authorJegga, Anil G.
dc.contributor.authorZhang, Jie
dc.contributor.authorJin, Victor X.
dc.contributor.authorAronow, Bruce J.
dc.contributor.authorWang, Qianben
dc.contributor.authorGroden, Joanna
dc.contributor.departmentMedical and Molecular Genetics, School of Medicineen_US
dc.date.accessioned2019-05-10T15:55:44Z
dc.date.available2019-05-10T15:55:44Z
dc.date.issued2018-07-27
dc.description.abstractMutation 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.en_US
dc.identifier.citationHankey, 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. doi:10.18632/oncotarget.25781en_US
dc.identifier.urihttps://hdl.handle.net/1805/19213
dc.language.isoen_USen_US
dc.publisherImpact Journalsen_US
dc.relation.isversionof10.18632/oncotarget.25781en_US
dc.relation.journalOncotargeten_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/3.0/us*
dc.sourcePMCen_US
dc.subjectAPCen_US
dc.subjectAP-1en_US
dc.subjectCanonical WNT signalingen_US
dc.subjectChromatinen_US
dc.subjectColorectal canceren_US
dc.titleChromatin-associated APC regulates gene expression in collaboration with canonical WNT signaling and AP-1en_US
dc.typeArticleen_US
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