Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing

Tian, A. et al. (2017) Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing. PLoS Genetics, 13(7), e1006870. (doi:10.1371/journal.pgen.1006870) (PMID:28708826) (PMCID:PMC5510812)

Tian, A. et al. (2017) Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing. PLoS Genetics, 13(7), e1006870. (doi:10.1371/journal.pgen.1006870) (PMID:28708826) (PMCID:PMC5510812)

[img]
Preview
Text
144283.pdf - Published Version
Available under License Creative Commons Attribution.

22MB

Abstract

Wnt/β-catenin signal transduction directs intestinal stem cell (ISC) proliferation during homeostasis. Hyperactivation of Wnt signaling initiates colorectal cancer, which most frequently results from truncation of the tumor suppressor Adenomatous polyposis coli (APC). The β-catenin-TCF transcription complex activates both the physiological expression of Wnt target genes in the normal intestinal epithelium and their aberrantly increased expression in colorectal tumors. Whether mechanistic differences in the Wnt transcription machinery drive these distinct levels of target gene activation in physiological versus pathological states remains uncertain, but is relevant for the design of new therapeutic strategies. Here, using a Drosophila model, we demonstrate that two evolutionarily conserved transcription cofactors, Earthbound (Ebd) and Erect wing (Ewg), are essential for all major consequences of Apc1 inactivation in the intestine: the hyperactivation of Wnt target gene expression, excess number of ISCs, and hyperplasia of the epithelium. In contrast, only Ebd, but not Ewg, mediates the Wnt-dependent regulation of ISC proliferation during homeostasis. Therefore, in the adult intestine, Ebd acts independently of Ewg in physiological Wnt signaling, but cooperates with Ewg to induce the hyperactivation of Wnt target gene expression following Apc1 loss. These findings have relevance for human tumorigenesis, as Jerky (JRK/JH8), the human Ebd homolog, promotes Wnt pathway hyperactivation and is overexpressed in colorectal, breast, and ovarian cancers. Together, our findings reveal distinct requirements for Ebd and Ewg in physiological Wnt pathway activation versus oncogenic Wnt pathway hyperactivation following Apc1 loss. Such differentially utilized transcription cofactors may offer new opportunities for the selective targeting of Wnt-driven cancers.

Item Type:Articles
Keywords:Research article, biology and life sciences, medicine and health sciences, research and analysis methods.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Perochon, Miss Jessica and Kalna, Dr Gabriela and Cordero, Dr Julia and Sansom, Professor Owen
Authors: Tian, A., Benchabane, H., Wang, Z., Zimmerman, C., Xin, N., Perochon, J., Kalna, G., Sansom, O. J., Cheng, C., Cordero, J. B., and Ahmed, Y.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7390
ISSN (Online):1553-7404
Copyright Holders:Copyright © 2017 Tian et al.
First Published:First published in PLoS Genetics 13(7):e1006870
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
633021Regulation of stem cell function during tissue homeostasis and transformationJulia CorderoWellcome Trust (WELLCOTR)104103/Z/14/ZRI CANCER SCIENCES