Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing.
Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing.
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DOI：
10.1371/journal.pgen.1006870
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发表时间：
2017-07
期刊：
影响因子：
4.5
通讯作者：
Ahmed Y
中科院分区：
文献类型：
--
作者：
Tian A;Benchabane H;Wang Z;Zimmerman C;Xin N;Perochon J;Kalna G;Sansom OJ;Cheng C;Cordero JB;Ahmed Y
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. The identification of effective therapy for colorectal cancer, which is a leading cause of cancer-related death, is imperative. Wnt pathway components have promise as therapeutic targets, since more than 90% of colon cancers are triggered by mutations that overactivate this pathway, particularly in the tumor suppressor APC. However, as Wnt signaling is also required for normal intestinal homeostasis, the selective therapeutic targeting of oncogenic Wnt signaling remains a major challenge. Through a forward genetic screen, we previously identified two suppressors of Drosophila Apc1, Earthbound (Ebd) and Erect wing (Ewg), as transcription cofactors of the Wnt pathway. Here, we analyze the roles of these two factors in the Wnt-dependent control of intestinal stem cell proliferation. We find that both Ebd and Ewg are essential for the hyperactivation of Wnt signaling and the consequent epithelial hyperplasia resulting from Apc1 inactivation. Moreover, Ebd, but not Ewg, is also required for the Wnt-dependent maintenance of normal intestinal homeostasis. Together, our findings reveal differential requirements for two highly conserved transcriptional cofactors in Wnt pathway activation versus hyperactivation. The identification of such factors may provide potential selectivity for the targeting of Wnt-driven cancers.
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